The lab’s research is helped by the strong commitment in developing new tools.
IRIS-CC Omics
The IRIS-CC Omics Tools Hub is a centralized platform that provides user-friendly tools and scripts for analyzing complex omics data. It offers accessible resources across key areas of bioinformatics, including transcriptomics, multi-omics integration, and artificial intelligence applications. Users can access step-by-step workflows for single-cell RNA-seq and gene expression analysis, along with practical solutions for integrating transcriptomic, proteomic, and epigenomic data. The platform also features pre-built machine learning and deep learning models, enabling users to implement predictive analytics without the need for extensive coding experience.
SBMOpenMM
SBMOpenMM is a Python library to run protein structure-based model (SBM) simulations using OpenMM toolkit. The library offers flexibility for creating SBM force fields that can be customised to capture different aspects of protein SBM potential energy exploration.
See more details here.
Floor, Martin
Development of a framework for the computational design and evolution of enzymes PhD Thesis
2022.
@phdthesis{Floor2022,
title = {Development of a framework for the computational design and evolution of enzymes},
author = {Martin Floor},
url = {https://www.tdx.cat/handle/10803/674584},
year = {2022},
date = {2022-02-07},
urldate = {2022-02-07},
abstract = {Enzymatic design is at the heart of modern biotechnology and, increasingly so, the so-called fine chemistry and green chemistry. Designing enzymes for applications in industrial or bioremediation contexts, for example, involves having a deep knowledge of enzymatic systems to propose rational changes that improve their catalytic properties. In recent years, a large number of computational methods have been developed to design or improve new enzymes. However, achieving enzymatic predictions through these methods to reach the power of natural enzymes is still an unattained scientific challenge.
In this thesis, we propose the combination of two robust methodologies to devise a computational framework for enzyme design and evolution. On the one hand, a successful protein design methodology— the Rosetta modelling environment— and on the other, an efficient method for evaluating chemical reactivity based on molecular simulations— the Empirical Valence Bond method. Both tools, working collectively, are an attractive proposition for tackling state-of-the-art challenges in the field of enzymatic design.
After applying our methodology in a proof-of-concept chemical system, the catalytic reaction of Kemp eliminase, we found a series of obstacles that need to be addressed before creating a successful framework for the computational design and evolution of enzymes. This work explores these challenges in-depth and suggests new directions to improve different aspects of the proposed methodology. Specifically, on the one hand, we make a careful dissection of the interaction energies provided by Rosetta, a key aspect for a better prediction of structural frames (or scaffolds) on which to build new enzymatic designs. On the other hand, we propose a new practical implementation of a structure-based simulation model in the OpenMM package of molecular simulations. Both elements are a critical step in achieving an efficient and robust "toolbox" for exploring the structure-function map of designed enzymes.
},
keywords = {},
pubstate = {published},
tppubtype = {phdthesis}
}
Enzymatic design is at the heart of modern biotechnology and, increasingly so, the so-called fine chemistry and green chemistry. Designing enzymes for applications in industrial or bioremediation contexts, for example, involves having a deep knowledge of enzymatic systems to propose rational changes that improve their catalytic properties. In recent years, a large number of computational methods have been developed to design or improve new enzymes. However, achieving enzymatic predictions through these methods to reach the power of natural enzymes is still an unattained scientific challenge.
In this thesis, we propose the combination of two robust methodologies to devise a computational framework for enzyme design and evolution. On the one hand, a successful protein design methodology— the Rosetta modelling environment— and on the other, an efficient method for evaluating chemical reactivity based on molecular simulations— the Empirical Valence Bond method. Both tools, working collectively, are an attractive proposition for tackling state-of-the-art challenges in the field of enzymatic design.
After applying our methodology in a proof-of-concept chemical system, the catalytic reaction of Kemp eliminase, we found a series of obstacles that need to be addressed before creating a successful framework for the computational design and evolution of enzymes. This work explores these challenges in-depth and suggests new directions to improve different aspects of the proposed methodology. Specifically, on the one hand, we make a careful dissection of the interaction energies provided by Rosetta, a key aspect for a better prediction of structural frames (or scaffolds) on which to build new enzymatic designs. On the other hand, we propose a new practical implementation of a structure-based simulation model in the OpenMM package of molecular simulations. Both elements are a critical step in achieving an efficient and robust "toolbox" for exploring the structure-function map of designed enzymes.
In this thesis, we propose the combination of two robust methodologies to devise a computational framework for enzyme design and evolution. On the one hand, a successful protein design methodology— the Rosetta modelling environment— and on the other, an efficient method for evaluating chemical reactivity based on molecular simulations— the Empirical Valence Bond method. Both tools, working collectively, are an attractive proposition for tackling state-of-the-art challenges in the field of enzymatic design.
After applying our methodology in a proof-of-concept chemical system, the catalytic reaction of Kemp eliminase, we found a series of obstacles that need to be addressed before creating a successful framework for the computational design and evolution of enzymes. This work explores these challenges in-depth and suggests new directions to improve different aspects of the proposed methodology. Specifically, on the one hand, we make a careful dissection of the interaction energies provided by Rosetta, a key aspect for a better prediction of structural frames (or scaffolds) on which to build new enzymatic designs. On the other hand, we propose a new practical implementation of a structure-based simulation model in the OpenMM package of molecular simulations. Both elements are a critical step in achieving an efficient and robust "toolbox" for exploring the structure-function map of designed enzymes.
Floor, Martin; Li, Kengjie; Estevez-Gay, Miquel; Agulló, Luis; Muñoz-Torres, Pau Marc; Hwang, Jenn K; Osuna, Sílvia; Villà-Freixa, Jordi
SBMOpenMM: A Builder of Structure-Based Models for OpenMM Journal Article
In: J Chem Inf Model, vol. 61, no. 7, pp. 3166-3171, 2021, ISSN: 1549-960X.
@article{Floor2021,
title = {SBMOpenMM: A Builder of Structure-Based Models for OpenMM},
author = {Martin Floor and Kengjie Li and Miquel Estevez-Gay and Luis Agulló and Pau Marc Muñoz-Torres and Jenn K Hwang and Sílvia Osuna and Jordi Villà-Freixa},
url = {https://pubmed.ncbi.nlm.nih.gov/34251801/},
doi = {10.1021/acs.jcim.1c00122},
issn = {1549-960X},
year = {2021},
date = {2021-07-26},
urldate = {2021-07-26},
journal = {J Chem Inf Model},
volume = {61},
number = {7},
pages = {3166-3171},
abstract = {Molecular dynamics (MD) simulations have become a standard tool to correlate the structure and function of biomolecules and significant advances have been made in the study of proteins and their complexes. A major drawback of conventional MD simulations is the difficulty and cost of obtaining converged results, especially when exploring potential energy surfaces containing considerable energy barriers. This limits the wide use of MD calculations to determine the thermodynamic properties of biomolecular processes. Indeed, this is true when considering the conformational entropy of such processes, which is ultimately critical in assessing the simulations' convergence. Alternatively, a wide range of structure-based models (SBMs) has been used in the literature to unravel the basic mechanisms of biomolecular dynamics. These models introduce simplifications that focus on the relevant aspects of the physical process under study. Because of this, SBMs incorporate the need to modify the force field definition and parameters to target specific biophysical simulations. Here we introduce SBMOpenMM, a Python library to build force fields for SBMs, that uses the OpenMM framework to create and run SBM simulations. The code is flexible and user-friendly and profits from the high customizability and performance provided by the OpenMM platform.},
keywords = {},
pubstate = {published},
tppubtype = {article}
}
Molecular dynamics (MD) simulations have become a standard tool to correlate the structure and function of biomolecules and significant advances have been made in the study of proteins and their complexes. A major drawback of conventional MD simulations is the difficulty and cost of obtaining converged results, especially when exploring potential energy surfaces containing considerable energy barriers. This limits the wide use of MD calculations to determine the thermodynamic properties of biomolecular processes. Indeed, this is true when considering the conformational entropy of such processes, which is ultimately critical in assessing the simulations' convergence. Alternatively, a wide range of structure-based models (SBMs) has been used in the literature to unravel the basic mechanisms of biomolecular dynamics. These models introduce simplifications that focus on the relevant aspects of the physical process under study. Because of this, SBMs incorporate the need to modify the force field definition and parameters to target specific biophysical simulations. Here we introduce SBMOpenMM, a Python library to build force fields for SBMs, that uses the OpenMM framework to create and run SBM simulations. The code is flexible and user-friendly and profits from the high customizability and performance provided by the OpenMM platform.
Adun
Adun is a new extendible molecular simulation program that also includes data management and analysis capabilities. The Adun molecular simulation application has been designed from the ground up to cater for a broad range of users and needs, from computational chemists to experimental biologists. Adun provides advanced algorithms and protocols for molecular simulation which can be accessed from an intuitive user interface but also from a more flexible programmatic level. It is built on the Adun framework which is a powerful library for creating and manipulating simulations. However it goes beyond just performing simulations by incorporating tools for analysis and management of simulation data aswell as providing mechanisms that allow the easy extension of its abilities. In many senses Adun is simply a structure that can incorporate any molecular simulation tools allowing it almost unlimited potential for growth.
Drechsel, Nils Jan Daniel
Development of a multiscale protocol for the study of energetics of protein dymanics PhD Thesis
Universitat Pompeu Fabra, 2013.
@phdthesis{Nils2013,
title = {Development of a multiscale protocol for the study of energetics of protein dymanics},
author = {Nils Jan Daniel Drechsel},
url = {http://www.tdx.cat/handle/10803/125071},
year = {2013},
date = {2013-01-01},
urldate = {2013-01-01},
school = {Universitat Pompeu Fabra},
abstract = {Multiscale Molecular Dynamics is a popular trend in the field of computational chemistry and physics. Coarse-grained force-fields have been around for years, and used independently, but used cooperatively with all-atom force-fields combines their advantages and cancels their disadvantages. This seems to be the case, however, only when they are both compatible. In this thesis, a Multiscale Molecular Dynamics Protocol is introduced, based on earlier work by Benjamin Messer, Z. Fan, Arieh Warshel, and in other parts by Christopher Fennel and Ken Dill. The protocol consists of the following tool-set: * A parametrization machinery that created a new coarse-grained force-field named AmberCG. * A multiscale thermodynamic cycle utilized within a free energy perturbation context to cooperatively use the best of coarse-grained and all-atom force-fields. * A collective variable that performs a linearization of the phase space to improve separation of product and reactant states. * A new algorithm to calculate functional quantities on spheres bounded by complicated solvent accessible surface areas - which as a special case calculates the amount of solvent accessible surface area. * A novel algorithm based on simple one dimensional Depth-Buffers, to identify atoms which actively form the boundary of the solvent accessible surface areas. Executing the protocol involves the following steps: 1. Construction of a coarse-grained force-field, based on an all-atom force-field. This involves setting up coarse-grained potentials and optimization of their parameters against selected reference structures and conformations. 2. Parametrization of a solvation model which is compatible to the force-field. 3. Usage of the coarse-grained force-field to sample the conformational space of a reaction. 4. Correction of the coarse-grained results with an all-atom force-field. 5. Analysis of the results using appropriate collective coordinates. 6. Reiteration until accuracies are met. Alternatively, instead of using the methods in the protocol, they can be utilized stand-alone. They simplify calculations, thus provid- ing speed-ups, while at the same time aiming to maintain or improve accuracy. Of course, there is no free lunch, and often the methods will include inaccuracies that exceed an acceptable threshold. However, the multiscale protocol is meant to be seen as an iterative technique, in which deficiency can be detected, and the protocol adjusted to restore balance.},
keywords = {},
pubstate = {published},
tppubtype = {phdthesis}
}
Multiscale Molecular Dynamics is a popular trend in the field of computational chemistry and physics. Coarse-grained force-fields have been around for years, and used independently, but used cooperatively with all-atom force-fields combines their advantages and cancels their disadvantages. This seems to be the case, however, only when they are both compatible. In this thesis, a Multiscale Molecular Dynamics Protocol is introduced, based on earlier work by Benjamin Messer, Z. Fan, Arieh Warshel, and in other parts by Christopher Fennel and Ken Dill. The protocol consists of the following tool-set: * A parametrization machinery that created a new coarse-grained force-field named AmberCG. * A multiscale thermodynamic cycle utilized within a free energy perturbation context to cooperatively use the best of coarse-grained and all-atom force-fields. * A collective variable that performs a linearization of the phase space to improve separation of product and reactant states. * A new algorithm to calculate functional quantities on spheres bounded by complicated solvent accessible surface areas - which as a special case calculates the amount of solvent accessible surface area. * A novel algorithm based on simple one dimensional Depth-Buffers, to identify atoms which actively form the boundary of the solvent accessible surface areas. Executing the protocol involves the following steps: 1. Construction of a coarse-grained force-field, based on an all-atom force-field. This involves setting up coarse-grained potentials and optimization of their parameters against selected reference structures and conformations. 2. Parametrization of a solvation model which is compatible to the force-field. 3. Usage of the coarse-grained force-field to sample the conformational space of a reaction. 4. Correction of the coarse-grained results with an all-atom force-field. 5. Analysis of the results using appropriate collective coordinates. 6. Reiteration until accuracies are met. Alternatively, instead of using the methods in the protocol, they can be utilized stand-alone. They simplify calculations, thus provid- ing speed-ups, while at the same time aiming to maintain or improve accuracy. Of course, there is no free lunch, and often the methods will include inaccuracies that exceed an acceptable threshold. However, the multiscale protocol is meant to be seen as an iterative technique, in which deficiency can be detected, and the protocol adjusted to restore balance.
Ávila, César; Drechsel, Nils; Alcántara, Raúl; Villà-Freixa, Jordi
Multiscale Simulations of Protein Aggregation Journal Article
In: Curr. Prot. Pept. Sci., vol. 12, pp. 221–234, 2011.
@article{Avila2011,
title = {Multiscale Simulations of Protein Aggregation},
author = {César Ávila and Nils Drechsel and Raúl Alcántara and Jordi Villà-Freixa},
url = {http://www.ncbi.nlm.nih.gov/pubmed/21348836},
year = {2011},
date = {2011-01-01},
urldate = {2011-01-01},
journal = {Curr. Prot. Pept. Sci.},
volume = {12},
pages = {221--234},
keywords = {},
pubstate = {published},
tppubtype = {article}
}
Johnston, M A
Development of a Molecular Simulator and its Application to Conformational Changes in Biomolecules PhD Thesis
Universitat Pompeu Fabra, 2009.
@phdthesis{Johnston2009,
title = {Development of a Molecular Simulator and its Application to Conformational Changes in Biomolecules},
author = {M A Johnston},
url = {https://tdx.cat/handle/10803/7172?show=full},
year = {2009},
date = {2009-01-01},
urldate = {2009-01-01},
school = {Universitat Pompeu Fabra},
abstract = {This thesis deals with the creation of a new open-source program and
API for biomolecular simulation and its subsequent application to
biological problems. The program, Adun, focuses on the key areas
of biological free-energy calculations, rapid development and high-performance
productivity. Methods such as SCAAS, EVB and switched Generalised-Born
have been implemented to realise the first aim. The presence of these
techniques, along with a multitude of others, verifies Adun's rapid
development potential. All these features are united by an advanced
graphical user interface which provides novel capabibilities such
as inbuilt data management, and distributed datasharing and computation.
Adun's ability to tackle biological problems is illustrated with
an investigation of Ras dynamics and the development, implementation
and testing of a novel method for determining transition paths. In
addition to concretely demonstrating Adun's potential these studies
also provide insight into the use of dynamic information in elucidating
protein function. The current state of the program and the results
of the two studies is discussed and indications of future aims and
directions given. In addition personal thoughts on the role of computational
biologists as developers of applications, for themselves and the
wider scientific community, are provided},
keywords = {},
pubstate = {published},
tppubtype = {phdthesis}
}
This thesis deals with the creation of a new open-source program and
API for biomolecular simulation and its subsequent application to
biological problems. The program, Adun, focuses on the key areas
of biological free-energy calculations, rapid development and high-performance
productivity. Methods such as SCAAS, EVB and switched Generalised-Born
have been implemented to realise the first aim. The presence of these
techniques, along with a multitude of others, verifies Adun's rapid
development potential. All these features are united by an advanced
graphical user interface which provides novel capabibilities such
as inbuilt data management, and distributed datasharing and computation.
Adun's ability to tackle biological problems is illustrated with
an investigation of Ras dynamics and the development, implementation
and testing of a novel method for determining transition paths. In
addition to concretely demonstrating Adun's potential these studies
also provide insight into the use of dynamic information in elucidating
protein function. The current state of the program and the results
of the two studies is discussed and indications of future aims and
directions given. In addition personal thoughts on the role of computational
biologists as developers of applications, for themselves and the
wider scientific community, are provided
API for biomolecular simulation and its subsequent application to
biological problems. The program, Adun, focuses on the key areas
of biological free-energy calculations, rapid development and high-performance
productivity. Methods such as SCAAS, EVB and switched Generalised-Born
have been implemented to realise the first aim. The presence of these
techniques, along with a multitude of others, verifies Adun's rapid
development potential. All these features are united by an advanced
graphical user interface which provides novel capabibilities such
as inbuilt data management, and distributed datasharing and computation.
Adun's ability to tackle biological problems is illustrated with
an investigation of Ras dynamics and the development, implementation
and testing of a novel method for determining transition paths. In
addition to concretely demonstrating Adun's potential these studies
also provide insight into the use of dynamic information in elucidating
protein function. The current state of the program and the results
of the two studies is discussed and indications of future aims and
directions given. In addition personal thoughts on the role of computational
biologists as developers of applications, for themselves and the
wider scientific community, are provided
Johnston, M A; Villà-Freixa, J
Enabling Data Sharing and Collaboration in Complex Systems Applications Journal Article
In: Distributed, High-Performance and Grid Computing in Computational Biology (GCCB 2007) , vol. 4360, pp. 124–140, 2007, ISBN: 978-3-540-69841-8.
@article{Johnston2007,
title = {Enabling Data Sharing and Collaboration in Complex Systems Applications},
author = {M A Johnston and J Villà-Freixa},
editor = {Werner Dubitzky, Assaf Schuster, Peter M. A. Sloot, Michael Schroeder, Mathilde Romberg },
url = {http://www.springerlink.com/content/9476700461j37732},
doi = {10.1007/978-3-540-69968-2_10},
isbn = {978-3-540-69841-8},
year = {2007},
date = {2007-01-01},
urldate = {2007-01-01},
journal = {Distributed, High-Performance and Grid Computing in Computational Biology (GCCB 2007) },
volume = {4360},
pages = {124--140},
abstract = {We describe a model for the data storage, retrieval and manipulation requirements of complex system applications based on pervasive, integrated, application specific databases shared over a peer to peer network. Such a model can significannotly increase productivity through transparent data sharing and querying as well as aid collaborations. We show a proof of concept of this approach as implemented in the Adun molecular simulation application together with a discussion of its limitations and possible extensions.},
keywords = {},
pubstate = {published},
tppubtype = {article}
}
We describe a model for the data storage, retrieval and manipulation requirements of complex system applications based on pervasive, integrated, application specific databases shared over a peer to peer network. Such a model can significannotly increase productivity through transparent data sharing and querying as well as aid collaborations. We show a proof of concept of this approach as implemented in the Adun molecular simulation application together with a discussion of its limitations and possible extensions.
Charlot, Magali; de Fabritiis, Gianni; García--Lomana, Adrián L; Gómez--Garrido, Àlex; Groen, Derek; Gulyás, Laszlo; Hoekstra, Alfons; Johnston, Michael A; Kampis, George; Zwart, G; Robinson, Steve; Strathern, Mark; Swain, Martin; Szemes, Gábor; Villà-Freixa, Jordi
The QosCosGrid project: Quasi-opportunistic supercomputing for complex systems simulations. description of a general framework from different types of applications. Proceedings Article
In: Proceedings of Ibergrid 2007 conference, Santiago de Compostela, 2007.
@inproceedings{Charlot2007,
title = {The QosCosGrid project: Quasi-opportunistic supercomputing for complex systems simulations. description of a general framework from different types of applications.},
author = {Magali Charlot and Gianni de Fabritiis and Adrián L García--Lomana and Àlex Gómez--Garrido and Derek Groen and Laszlo Gulyás and Alfons Hoekstra and Michael A Johnston and George Kampis and G Zwart and Steve Robinson and Mark Strathern and Martin Swain and Gábor Szemes and Jordi Villà-Freixa},
year = {2007},
date = {2007-01-01},
urldate = {2007-01-01},
booktitle = {Proceedings of Ibergrid 2007 conference},
address = {Santiago de Compostela},
keywords = {},
pubstate = {published},
tppubtype = {inproceedings}
}
Johnston, Michael A; Galván, Ignacio Fdez; Villà-Freixa, Jordi
Framework-based design of a new all-purpose molecular simulation application: the Adun simulator. Journal Article
In: J Comput Chem, vol. 26, no. 15, pp. 1647–1659, 2005.
@article{Johnston2005b,
title = {Framework-based design of a new all-purpose molecular simulation application: the Adun simulator.},
author = {Michael A Johnston and Ignacio Fdez Galván and Jordi Villà-Freixa},
url = {http://dx.doi.org/10.1002/jcc.20312},
doi = {10.1002/jcc.20312},
year = {2005},
date = {2005-11-01},
urldate = {2005-11-01},
journal = {J Comput Chem},
volume = {26},
number = {15},
pages = {1647--1659},
institution = {Computational Biochemistry and Biophysics Laboratory, Research Group on Biomedical Informatics (GRIB), Institut Municipal d'Investigaci Mdica and Universitat Pompeu Fabra, C/Doctor Aiguader, 80 08003 Barcelona, Catalunya, Spain.},
abstract = {Here we present Adun, a new molecular simulator that represents a
paradigm shift in the way scientific programs are developed. The
traditional algorithm centric methods of scientific programming can
lead to major maintainability and productivity problems when developing
large complex programs. These problems have long been recognized
by computer scientists; however, the ideas and techniques developed
to deal with them have not achieved widespread adoption in the scientific
community. Adun is the result of the application of these ideas,
including pervasive polymorphism, evolutionary frameworks, and refactoring,
to the molecular simulation domain. The simulator itself is underpinned
by the Adun Framework, which separates the structure of the program
from any underlying algorithms, thus giving a completely reusable
design. The aims are twofold. The first is to provide a platform
for rapid development and implementation of different simulation
types and algorithms. The second is to decrease the learning barrier
for new developers by providing a rigorous and well-defined structure.
We present some examples on the use of Adun by performing simple
free-energy simulations for the adiabatic charging of a single ion,
using both free-energy perturbation and the Bennett's method. We
also illustrate the power of the design by detailing the ease with
which ASEP/MD, an elaborated mean field QM/MM method originally written
in FORTRAN 90, was implemented into Adun.},
keywords = {},
pubstate = {published},
tppubtype = {article}
}
Here we present Adun, a new molecular simulator that represents a
paradigm shift in the way scientific programs are developed. The
traditional algorithm centric methods of scientific programming can
lead to major maintainability and productivity problems when developing
large complex programs. These problems have long been recognized
by computer scientists; however, the ideas and techniques developed
to deal with them have not achieved widespread adoption in the scientific
community. Adun is the result of the application of these ideas,
including pervasive polymorphism, evolutionary frameworks, and refactoring,
to the molecular simulation domain. The simulator itself is underpinned
by the Adun Framework, which separates the structure of the program
from any underlying algorithms, thus giving a completely reusable
design. The aims are twofold. The first is to provide a platform
for rapid development and implementation of different simulation
types and algorithms. The second is to decrease the learning barrier
for new developers by providing a rigorous and well-defined structure.
We present some examples on the use of Adun by performing simple
free-energy simulations for the adiabatic charging of a single ion,
using both free-energy perturbation and the Bennett's method. We
also illustrate the power of the design by detailing the ease with
which ASEP/MD, an elaborated mean field QM/MM method originally written
in FORTRAN 90, was implemented into Adun.
paradigm shift in the way scientific programs are developed. The
traditional algorithm centric methods of scientific programming can
lead to major maintainability and productivity problems when developing
large complex programs. These problems have long been recognized
by computer scientists; however, the ideas and techniques developed
to deal with them have not achieved widespread adoption in the scientific
community. Adun is the result of the application of these ideas,
including pervasive polymorphism, evolutionary frameworks, and refactoring,
to the molecular simulation domain. The simulator itself is underpinned
by the Adun Framework, which separates the structure of the program
from any underlying algorithms, thus giving a completely reusable
design. The aims are twofold. The first is to provide a platform
for rapid development and implementation of different simulation
types and algorithms. The second is to decrease the learning barrier
for new developers by providing a rigorous and well-defined structure.
We present some examples on the use of Adun by performing simple
free-energy simulations for the adiabatic charging of a single ion,
using both free-energy perturbation and the Bennett's method. We
also illustrate the power of the design by detailing the ease with
which ASEP/MD, an elaborated mean field QM/MM method originally written
in FORTRAN 90, was implemented into Adun.
ByoDyn
In systems biology it is becoming a routine task to build models of increasing complexity on a given biochemical network or pathway of interest. One of the main problems in building such models is the determination of the parameters underlying each modelled process. ByoDyn has been designed to provide an easily extendable computational framework to estimate and analyze parameters in highly uncharacterized models.
de Lomana, Adrián López García
Universitat Pompeu Fabra, 2010, ISBN: 978-84-694-2117-8.
@phdthesis{Lopez2010,
title = {Computational Approaches to the Modelling of Topological and Dynamical Aspects of Biochemical Networks},
author = {Adrián López García de Lomana},
url = {http://hdl.handle.net/10803/7224},
isbn = {978-84-694-2117-8},
year = {2010},
date = {2010-01-01},
urldate = {2010-01-01},
school = {Universitat Pompeu Fabra},
abstract = {Regulatory mechanisms of cells can be modelled to control and understand
cellular biology. Di¿ent levels of abstraction are used to describe
biological processes. In this work we have used graphs and di¿ential
equations to model cellular interactions qualitatively and quantitatively.
From di¿ent organisms, E. coli and S. cerevisiae, we have analysed
data available for they complete interaction and activity networks.
At the level of interaction, the protein-protein interaction network,
the transcriptional regulatory networks and the metabolic network
have been studied; for the activity, both gene and protein pro les
of the whole organism have been examined. From the rich variety of
graph measures, one of primer importance is the degree distribution.
I have applied statistical analysis tools to such biological networks
in order to characterise the degree distribution. In all cases the
studied degree distributions have a heavy-tailed shape, but most
of them present signi cant di¿ences from a power-law model according
to a statistical test. Moreover, none of the networks could be unequivocally
assigned to any of the tested distribution. On the other hand, in
a more ne-grained view, I have used di¿ential equations to model
dynamics of biochemical systems. First, a software tool called ByoDyn
has been created from scratch incorporating a fairly complete range
of analysis methods. Both deterministic and stochastic simulations
can be performed, models can be analysed by means of parameter estimation,
sensitivity, identi ability analysis, and optimal experimental design.
Moreover, a web interface has been created that provides with the
possibility interact with the program in a graphical manner, independent
of the user con guration, allowing the execution of the program at
di¿ent computational environments. Finally, we have applied a protocol
of optimal experimental design on a multicellular model of embryogenesis.},
keywords = {},
pubstate = {published},
tppubtype = {phdthesis}
}
Regulatory mechanisms of cells can be modelled to control and understand
cellular biology. Di¿ent levels of abstraction are used to describe
biological processes. In this work we have used graphs and di¿ential
equations to model cellular interactions qualitatively and quantitatively.
From di¿ent organisms, E. coli and S. cerevisiae, we have analysed
data available for they complete interaction and activity networks.
At the level of interaction, the protein-protein interaction network,
the transcriptional regulatory networks and the metabolic network
have been studied; for the activity, both gene and protein pro les
of the whole organism have been examined. From the rich variety of
graph measures, one of primer importance is the degree distribution.
I have applied statistical analysis tools to such biological networks
in order to characterise the degree distribution. In all cases the
studied degree distributions have a heavy-tailed shape, but most
of them present signi cant di¿ences from a power-law model according
to a statistical test. Moreover, none of the networks could be unequivocally
assigned to any of the tested distribution. On the other hand, in
a more ne-grained view, I have used di¿ential equations to model
dynamics of biochemical systems. First, a software tool called ByoDyn
has been created from scratch incorporating a fairly complete range
of analysis methods. Both deterministic and stochastic simulations
can be performed, models can be analysed by means of parameter estimation,
sensitivity, identi ability analysis, and optimal experimental design.
Moreover, a web interface has been created that provides with the
possibility interact with the program in a graphical manner, independent
of the user con guration, allowing the execution of the program at
di¿ent computational environments. Finally, we have applied a protocol
of optimal experimental design on a multicellular model of embryogenesis.
cellular biology. Di¿ent levels of abstraction are used to describe
biological processes. In this work we have used graphs and di¿ential
equations to model cellular interactions qualitatively and quantitatively.
From di¿ent organisms, E. coli and S. cerevisiae, we have analysed
data available for they complete interaction and activity networks.
At the level of interaction, the protein-protein interaction network,
the transcriptional regulatory networks and the metabolic network
have been studied; for the activity, both gene and protein pro les
of the whole organism have been examined. From the rich variety of
graph measures, one of primer importance is the degree distribution.
I have applied statistical analysis tools to such biological networks
in order to characterise the degree distribution. In all cases the
studied degree distributions have a heavy-tailed shape, but most
of them present signi cant di¿ences from a power-law model according
to a statistical test. Moreover, none of the networks could be unequivocally
assigned to any of the tested distribution. On the other hand, in
a more ne-grained view, I have used di¿ential equations to model
dynamics of biochemical systems. First, a software tool called ByoDyn
has been created from scratch incorporating a fairly complete range
of analysis methods. Both deterministic and stochastic simulations
can be performed, models can be analysed by means of parameter estimation,
sensitivity, identi ability analysis, and optimal experimental design.
Moreover, a web interface has been created that provides with the
possibility interact with the program in a graphical manner, independent
of the user con guration, allowing the execution of the program at
di¿ent computational environments. Finally, we have applied a protocol
of optimal experimental design on a multicellular model of embryogenesis.
de Lomana, López García A; Gómez-Garrido, À; Sportouch, D; Villà-Freixa, J
Optimal Experimental Design in the Modelling of Pattern Formation Journal Article
In: LNCS, vol. 5101, pp. 610-619, 2008.
@article{Lomana2008,
title = {Optimal Experimental Design in the Modelling of Pattern Formation},
author = {López García A de Lomana and À Gómez-Garrido and D Sportouch and J Villà-Freixa},
url = {https://link.springer.com/chapter/10.1007/978-3-540-69384-0_66},
year = {2008},
date = {2008-01-01},
urldate = {2008-01-01},
journal = {LNCS},
volume = {5101},
pages = {610-619},
keywords = {},
pubstate = {published},
tppubtype = {article}
}
MIPSim
MIPSim (Molecular Interaction Potential Similarity) is a computer package that calculates both quantum and classical MIPs of biomolecules and makes comparisons and superpositions based on them. The program is opensource although its development is currently discontinued in the lab. More efforts will be done in the (near?) future
Barbany, M
Universitat Pompeu Fabra, 2006.
@phdthesis{Barbany2006,
title = {Three-dimensional similarity of molecules with biological interest on the basis of molecular interaction potentials},
author = {M Barbany},
url = {https://www.tdx.cat/handle/10803/7146#page=3},
year = {2006},
date = {2006-01-01},
urldate = {2006-01-01},
school = {Universitat Pompeu Fabra},
abstract = {One of the most promising areas of biomedical and pharmaceutical research
is computer assisted molecular design, which is based on the modelization
of the chemical entities responsible of the pharmacological activity
and the search of mathematical models describing the relationship
between the physicochemical properties and the biological activity
of such entities. In general, the success of these techniques depends
critically on the quality of the molecular description and, in particular,
on the fact that this description should be appropiate to represent
the molecular interaction phenomenon that we intend to describe.
In this sense, methodologies based on the molecular interaction potential
(MIP) offer important advantages with respect to other techniques.
MIPs are interactions of the studied molecule with one or several
selected chemical entities and they are useful tools for the comparison
of series of compounds displaying related biological behaviours.
As it will be shown here, structure-activity studies benefit from
a detailed comparative analysis of MIP distributions of prospective
drugs. This project aims to develop tools for computer assisted molecular
design based on the characterization and comparison of MIPs of different
compounds. To this end, the molecular similarity program MIPSim (Molecular
Interaction Potentials Similarity analysis) (C´aceres et al., 16,
568-569, Bioinformatics, 2000) has been further developed and applied
to different biological and pharmacological problems. MIPSim analyzes
and compares MIP distributions of series of biomolecules. One of
the objectives of MIPSim is to obtain automatic structural alignments
of series of biomolecules based on their MIP distributions. This
can be used to stablish hypothesis about their relative orientation
at the functional site, which is sometimes non-evident when only
taking into account structural features. MIPSim can evaluate MIPs
by classical or quantum methods, thanks to its interfaces to programs
GRID and GAMESS respectively. This thesis includes four scientific
studies which demonstrate the applicability of MIP similarity through
MIPSim to study molecules of biological interest. MIPSim has been
used to study alignments of biomolecules, to explore the electrostatic
properties of enzymes and catalytic antibodies, to help in searching
MIP-based docking and finally, to perform a 3DQSAR study based on
a MIP alignment.},
keywords = {},
pubstate = {published},
tppubtype = {phdthesis}
}
One of the most promising areas of biomedical and pharmaceutical research
is computer assisted molecular design, which is based on the modelization
of the chemical entities responsible of the pharmacological activity
and the search of mathematical models describing the relationship
between the physicochemical properties and the biological activity
of such entities. In general, the success of these techniques depends
critically on the quality of the molecular description and, in particular,
on the fact that this description should be appropiate to represent
the molecular interaction phenomenon that we intend to describe.
In this sense, methodologies based on the molecular interaction potential
(MIP) offer important advantages with respect to other techniques.
MIPs are interactions of the studied molecule with one or several
selected chemical entities and they are useful tools for the comparison
of series of compounds displaying related biological behaviours.
As it will be shown here, structure-activity studies benefit from
a detailed comparative analysis of MIP distributions of prospective
drugs. This project aims to develop tools for computer assisted molecular
design based on the characterization and comparison of MIPs of different
compounds. To this end, the molecular similarity program MIPSim (Molecular
Interaction Potentials Similarity analysis) (C´aceres et al., 16,
568-569, Bioinformatics, 2000) has been further developed and applied
to different biological and pharmacological problems. MIPSim analyzes
and compares MIP distributions of series of biomolecules. One of
the objectives of MIPSim is to obtain automatic structural alignments
of series of biomolecules based on their MIP distributions. This
can be used to stablish hypothesis about their relative orientation
at the functional site, which is sometimes non-evident when only
taking into account structural features. MIPSim can evaluate MIPs
by classical or quantum methods, thanks to its interfaces to programs
GRID and GAMESS respectively. This thesis includes four scientific
studies which demonstrate the applicability of MIP similarity through
MIPSim to study molecules of biological interest. MIPSim has been
used to study alignments of biomolecules, to explore the electrostatic
properties of enzymes and catalytic antibodies, to help in searching
MIP-based docking and finally, to perform a 3DQSAR study based on
a MIP alignment.
is computer assisted molecular design, which is based on the modelization
of the chemical entities responsible of the pharmacological activity
and the search of mathematical models describing the relationship
between the physicochemical properties and the biological activity
of such entities. In general, the success of these techniques depends
critically on the quality of the molecular description and, in particular,
on the fact that this description should be appropiate to represent
the molecular interaction phenomenon that we intend to describe.
In this sense, methodologies based on the molecular interaction potential
(MIP) offer important advantages with respect to other techniques.
MIPs are interactions of the studied molecule with one or several
selected chemical entities and they are useful tools for the comparison
of series of compounds displaying related biological behaviours.
As it will be shown here, structure-activity studies benefit from
a detailed comparative analysis of MIP distributions of prospective
drugs. This project aims to develop tools for computer assisted molecular
design based on the characterization and comparison of MIPs of different
compounds. To this end, the molecular similarity program MIPSim (Molecular
Interaction Potentials Similarity analysis) (C´aceres et al., 16,
568-569, Bioinformatics, 2000) has been further developed and applied
to different biological and pharmacological problems. MIPSim analyzes
and compares MIP distributions of series of biomolecules. One of
the objectives of MIPSim is to obtain automatic structural alignments
of series of biomolecules based on their MIP distributions. This
can be used to stablish hypothesis about their relative orientation
at the functional site, which is sometimes non-evident when only
taking into account structural features. MIPSim can evaluate MIPs
by classical or quantum methods, thanks to its interfaces to programs
GRID and GAMESS respectively. This thesis includes four scientific
studies which demonstrate the applicability of MIP similarity through
MIPSim to study molecules of biological interest. MIPSim has been
used to study alignments of biomolecules, to explore the electrostatic
properties of enzymes and catalytic antibodies, to help in searching
MIP-based docking and finally, to perform a 3DQSAR study based on
a MIP alignment.
Barbany, Montserrat; Gutiérrez-de-Terán, Hugo; Sanz, Ferran; Villà-Freixa, Jordi
Towards a MIP-based alignment and docking in computer-aided drug design. Journal Article
In: Proteins, vol. 56, no. 3, pp. 585–594, 2004.
@article{Barbany2004b,
title = {Towards a MIP-based alignment and docking in computer-aided drug design.},
author = {Montserrat Barbany and Hugo Gutiérrez-de-Terán and Ferran Sanz and Jordi Villà-Freixa},
url = {http://dx.doi.org/10.1002/prot.20153},
doi = {10.1002/prot.20153},
year = {2004},
date = {2004-08-01},
urldate = {2004-08-01},
journal = {Proteins},
volume = {56},
number = {3},
pages = {585--594},
institution = {Research Group on Biomedical Informatics (GRIB)-IMIM/UPF, Barcelona, Spain.},
abstract = {Structural alignment of ligands in their biological conformation is
a crucial step in the building of pharmacophoric models in structure-based
drug design. In addition, docking algorithms are limited in some
cases by the quality of the scoring functions and the limited flexibility
of the environment that the different programs allow. On the other
hand, GRID molecular interaction potentials (MIPs) have been used
for a long time in 3D-QSAR studies. However, in most of these studies
the alignment of the molecules is performed on the basis of geometrical
or physico-chemical criteria that differ from the MIPs used in the
partial least squares statistical analysis. We have previously developed
a method to use the same scoring function for the molecular alignment
and for 3D-QSAR studies. This methodology, based on the use of GRID
potentials, consists in the weighted averaging of similarities of
the relevant MIPs of the molecules to be aligned. Here we present
a method to obtain the weights for the different GRID probes in the
average based on the structural information on protein-ligand complexes
for relevant systems. The method, implemented in MIPSIM, is shown
to yield good accuracy in the prediction of the alignments for two
systems: a set of three inhibitors of dihydrofolate reductase and
a set of fifteen non-nucleoside HIV-1 reverse transcriptase inhibitors
(NNRTIs). The smooth GRID potentials are shown to capture the flexible
character of the active site, as opposed to traditional docking scoring
energy functions.},
keywords = {},
pubstate = {published},
tppubtype = {article}
}
Structural alignment of ligands in their biological conformation is
a crucial step in the building of pharmacophoric models in structure-based
drug design. In addition, docking algorithms are limited in some
cases by the quality of the scoring functions and the limited flexibility
of the environment that the different programs allow. On the other
hand, GRID molecular interaction potentials (MIPs) have been used
for a long time in 3D-QSAR studies. However, in most of these studies
the alignment of the molecules is performed on the basis of geometrical
or physico-chemical criteria that differ from the MIPs used in the
partial least squares statistical analysis. We have previously developed
a method to use the same scoring function for the molecular alignment
and for 3D-QSAR studies. This methodology, based on the use of GRID
potentials, consists in the weighted averaging of similarities of
the relevant MIPs of the molecules to be aligned. Here we present
a method to obtain the weights for the different GRID probes in the
average based on the structural information on protein-ligand complexes
for relevant systems. The method, implemented in MIPSIM, is shown
to yield good accuracy in the prediction of the alignments for two
systems: a set of three inhibitors of dihydrofolate reductase and
a set of fifteen non-nucleoside HIV-1 reverse transcriptase inhibitors
(NNRTIs). The smooth GRID potentials are shown to capture the flexible
character of the active site, as opposed to traditional docking scoring
energy functions.
a crucial step in the building of pharmacophoric models in structure-based
drug design. In addition, docking algorithms are limited in some
cases by the quality of the scoring functions and the limited flexibility
of the environment that the different programs allow. On the other
hand, GRID molecular interaction potentials (MIPs) have been used
for a long time in 3D-QSAR studies. However, in most of these studies
the alignment of the molecules is performed on the basis of geometrical
or physico-chemical criteria that differ from the MIPs used in the
partial least squares statistical analysis. We have previously developed
a method to use the same scoring function for the molecular alignment
and for 3D-QSAR studies. This methodology, based on the use of GRID
potentials, consists in the weighted averaging of similarities of
the relevant MIPs of the molecules to be aligned. Here we present
a method to obtain the weights for the different GRID probes in the
average based on the structural information on protein-ligand complexes
for relevant systems. The method, implemented in MIPSIM, is shown
to yield good accuracy in the prediction of the alignments for two
systems: a set of three inhibitors of dihydrofolate reductase and
a set of fifteen non-nucleoside HIV-1 reverse transcriptase inhibitors
(NNRTIs). The smooth GRID potentials are shown to capture the flexible
character of the active site, as opposed to traditional docking scoring
energy functions.
Rodrigo, J; Barbany, M; Gutiérrez-de-Terán, H; Centeno, N B; de Cáceres, Miquel; Dezi, Cristina; Fontaine, Fabien; Lozano, Juan José; Pastor, M; Villà, J; Sanz, F
Comparison of biomolecules on the basis of Molecular Interaction Potentials Journal Article
In: J. Braz. Chem. Soc., vol. 13, pp. 795-799, 2002.
@article{Rodrigo2002,
title = {Comparison of biomolecules on the basis of Molecular Interaction Potentials},
author = {J Rodrigo and M Barbany and H Gutiérrez-de-Terán and N B Centeno and Miquel de Cáceres and Cristina Dezi and Fabien Fontaine and Juan José Lozano and M Pastor and J Villà and F Sanz},
url = {http://www.scielo.br/scielo.php?script=sci_arttext&pid=S0103-50532002000600010},
doi = {10.1590/S0103-50532002000600010},
year = {2002},
date = {2002-01-01},
urldate = {2002-01-01},
journal = {J. Braz. Chem. Soc.},
volume = {13},
pages = {795-799},
keywords = {},
pubstate = {published},
tppubtype = {article}
}
Sanz, F; de Cáceres, M; Villà, J
Similarity analysis of Molecular Interaction Potential Distributions: The MIPSIM software Book Section
In: Carbó-Dorca, R (Ed.): The Fundamentals of Molecular Similarity, Kluwer Academic, 2002.
@incollection{Sanz2002,
title = {Similarity analysis of Molecular Interaction Potential Distributions: The MIPSIM software},
author = {F Sanz and M de Cáceres and J Villà},
editor = {R Carbó-Dorca},
year = {2002},
date = {2002-01-01},
urldate = {2002-01-01},
booktitle = {The Fundamentals of Molecular Similarity},
publisher = {Kluwer Academic},
keywords = {},
pubstate = {published},
tppubtype = {incollection}
}
de Cáceres, Miquel; Villà, Jordi; Lozano, Juan J; Sanz, Ferran
MIPSIM: similarity analysis of molecular interaction potentials Journal Article
In: Bioinformatics, vol. 16, no. 6, pp. 568-569, 2000.
@article{Caceres2000,
title = {MIPSIM: similarity analysis of molecular interaction potentials},
author = {Miquel de Cáceres and Jordi Villà and Juan J Lozano and Ferran Sanz},
url = {http://bioinformatics.oxfordjournals.org/cgi/content/abstract/16/6/568},
doi = {10.1093/bioinformatics/16.6.568},
year = {2000},
date = {2000-01-01},
urldate = {2000-01-01},
journal = {Bioinformatics},
volume = {16},
number = {6},
pages = {568-569},
abstract = {Summary: MIPSIM is a computational package designed to analyse and
compare 3D distributions of molecular interaction potentials (MIP)
of series of biomolecules. Availability: MIPSIM software is freely
distributed to non-profit academic institutions through its web site:
http://www1.imim.es/mipsim. Other organizations must contact the
developers. GAMESS (http://www.msg.ameslab.gov/GAMESS/GAMESS.html) and GRID (peter@biop.ox.ac.uk) are external software required to
perform some of the MIPSIM computations. They are obtained under conditions similar to MIPSIM's. Contact: mipsim@imim.es},
keywords = {},
pubstate = {published},
tppubtype = {article}
}
Summary: MIPSIM is a computational package designed to analyse and
compare 3D distributions of molecular interaction potentials (MIP)
of series of biomolecules. Availability: MIPSIM software is freely
distributed to non-profit academic institutions through its web site:
http://www1.imim.es/mipsim. Other organizations must contact the
developers. GAMESS (http://www.msg.ameslab.gov/GAMESS/GAMESS.html) and GRID (peter@biop.ox.ac.uk) are external software required to
perform some of the MIPSIM computations. They are obtained under conditions similar to MIPSIM's. Contact: mipsim@imim.es
compare 3D distributions of molecular interaction potentials (MIP)
of series of biomolecules. Availability: MIPSIM software is freely
distributed to non-profit academic institutions through its web site:
http://www1.imim.es/mipsim. Other organizations must contact the
developers. GAMESS (http://www.msg.ameslab.gov/GAMESS/GAMESS.html) and GRID (peter@biop.ox.ac.uk) are external software required to
perform some of the MIPSIM computations. They are obtained under conditions similar to MIPSIM's. Contact: mipsim@imim.es
Other software
Extensive work has been also carried out in a number of software tools for computational chemistry.
- MC-TINKERRATE: a program for multiconfigurational molecular mechanics.
Kim, Y; Corchado, J C; Villà, J; Xing, J; Truhlar, D G
Multiconfiguration Molecular Mechanics Algorithm for Potential Energy Surafces of Chemical Reactions Journal Article
In: J. Chem. Phys., vol. 112, pp. 2718-2735, 2000.
@article{Kim2000,
title = {Multiconfiguration Molecular Mechanics Algorithm for Potential Energy Surafces of Chemical Reactions},
author = {Y Kim and J C Corchado and J Villà and J Xing and D G Truhlar},
url = {http://jcp.aip.org/resource/1/jcpsa6/v112/i6/p2718_s1},
year = {2000},
date = {2000-01-01},
urldate = {2000-01-01},
journal = {J. Chem. Phys.},
volume = {112},
pages = {2718-2735},
keywords = {},
pubstate = {published},
tppubtype = {article}
}
- POLYRATE: a program for variational transition state theory (VTSTS) calculations.
Meana-Pañeda, Rubén; Zheng, Jingjing; Bao, Junwei Lucas; Zhang, Shuxia; Lynch, Benjamin J.; Corchado, José C.; Chuang, Yao-Yuan; Fast, Patton L.; Hu, Wei-Ping; Liu, Yi-Ping; Lynch, Gillian C.; Nguyen, Kiet A.; Jackels, Charles F.; Fernández-Ramos, Antonio; Ellingson, Benjamin A.; Melissas, Vasilios S.; Villà, Jordi; Rossi, Ivan; Coitiño, Elena L.; Pu, Jingzhi; Albu, Titus V.; Zhang, Rui Ming; Xu, Xuefei; Ratkiewicz, Artur; Steckler, Rozeanne; Garrett, Bruce C.; Isaacson, Alan D.; Truhlar, Donald G.
Polyrate 2023: A computer program for the calculation of chemical reaction rates for polyatomics. New version announcement Journal Article
In: Computer Physics Communications, vol. 294, pp. 108933, 2024, ISSN: 0010-4655.
@article{Meana-Pañeda2024,
title = {Polyrate 2023: A computer program for the calculation of chemical reaction rates for polyatomics. New version announcement},
author = {Rubén Meana-Pañeda and Jingjing Zheng and Junwei Lucas Bao and Shuxia Zhang and Benjamin J. Lynch and José C. Corchado and Yao-Yuan Chuang and Patton L. Fast and Wei-Ping Hu and Yi-Ping Liu and Gillian C. Lynch and Kiet A. Nguyen and Charles F. Jackels and Antonio Fernández-Ramos and Benjamin A. Ellingson and Vasilios S. Melissas and Jordi Villà and Ivan Rossi and Elena L. Coitiño and Jingzhi Pu and Titus V. Albu and Rui Ming Zhang and Xuefei Xu and Artur Ratkiewicz and Rozeanne Steckler and Bruce C. Garrett and Alan D. Isaacson and Donald G. Truhlar},
url = {https://www.sciencedirect.com/science/article/pii/S0010465523002783},
doi = {10.1016/j.cpc.2023.108933},
issn = {0010-4655},
year = {2024},
date = {2024-01-01},
urldate = {2024-01-01},
journal = {Computer Physics Communications},
volume = {294},
pages = {108933},
abstract = {Polyrate is a suite of computer programs for the calculation of chemical reaction rates of polyatomic species (including atoms and diatoms as special cases) by variational transition state theory (VTST); conventional transition state theory is also supported. Polyrate can calculate the rate constants for both bimolecular reactions and unimolecular reactions, and it can be applied to reactions in the gas phase, liquid solution phase, or solid state and to reactions at gas–solid interfaces. Polyrate can perform VTST calculations on gas-phase reactions with both tight and loose transition states. For tight transition states it uses the reaction-path (RP) variational transition state theory developed by Garrett and Truhlar, and for loose transition states it uses variable-reaction-coordinate (VRC) variational transition state theory developed by Georgievskii and Klippenstein. The RP methods used for tight transition states are conventional transition state theory, canonical variational transition state theory (CVT), and microcanonical variational transition state theory (μVT) with multidimensional semiclassical approximations for tunneling and nonclassical reflection. For VRC calculations, rate constants may be calculated for canonical or microcanonical ensembles or energy- and total-angular-momentum resolved microcanonical ensembles. Pressure-dependent rate constants for elementary reactions can be computed using system-specific quantum RRK theory (SS-QRRK) with the information obtained from high-pressure-limit VTST calculation as input by using the SS-QRRK utility code. Alternatively, Polyrate 2023 may be interfaced with TUMME 2023 for a master-equation treatment of pressure dependence or to obtain phenomenological rate constants for complex mechanisms. Potential energy surfaces may be analytic functions evaluated by subroutines, or they may be implicit surfaces defined by electronic structure input files or interface subroutines containing energies, gradients, and force constants (Hessians). For the latter, Polyrate can be used in conjunction with various interfaces to electronic structure programs for direct dynamics, and it has routines designed to make such interfacing straightforward. Polyrate supports six options for direct dynamics, namely (i) straight single-level direct dynamics, (ii) zero-order interpolated variational transition state theory (IVTST-0), (iii) first-order interpolated variational transition state theory (IVTST-1), (iv) interpolated variational transition state theory by mapping (IVTST-M), (v) variational transition state theory with interpolated single-point energies (VTST-ISPE), and (vi) variational transition state theory with interpolated optimized corrections (VTST-IOC). Polyrate can handle multistructural and torsional-potential anharmonicity in conjunction with the MSTor program. Polyrate 2023 contains 112 test runs, and 46 of these are for direct dynamics calculations; 85 of the test runs are single-level runs, and 27 are dual-level calculations.},
keywords = {},
pubstate = {published},
tppubtype = {article}
}
Polyrate is a suite of computer programs for the calculation of chemical reaction rates of polyatomic species (including atoms and diatoms as special cases) by variational transition state theory (VTST); conventional transition state theory is also supported. Polyrate can calculate the rate constants for both bimolecular reactions and unimolecular reactions, and it can be applied to reactions in the gas phase, liquid solution phase, or solid state and to reactions at gas–solid interfaces. Polyrate can perform VTST calculations on gas-phase reactions with both tight and loose transition states. For tight transition states it uses the reaction-path (RP) variational transition state theory developed by Garrett and Truhlar, and for loose transition states it uses variable-reaction-coordinate (VRC) variational transition state theory developed by Georgievskii and Klippenstein. The RP methods used for tight transition states are conventional transition state theory, canonical variational transition state theory (CVT), and microcanonical variational transition state theory (μVT) with multidimensional semiclassical approximations for tunneling and nonclassical reflection. For VRC calculations, rate constants may be calculated for canonical or microcanonical ensembles or energy- and total-angular-momentum resolved microcanonical ensembles. Pressure-dependent rate constants for elementary reactions can be computed using system-specific quantum RRK theory (SS-QRRK) with the information obtained from high-pressure-limit VTST calculation as input by using the SS-QRRK utility code. Alternatively, Polyrate 2023 may be interfaced with TUMME 2023 for a master-equation treatment of pressure dependence or to obtain phenomenological rate constants for complex mechanisms. Potential energy surfaces may be analytic functions evaluated by subroutines, or they may be implicit surfaces defined by electronic structure input files or interface subroutines containing energies, gradients, and force constants (Hessians). For the latter, Polyrate can be used in conjunction with various interfaces to electronic structure programs for direct dynamics, and it has routines designed to make such interfacing straightforward. Polyrate supports six options for direct dynamics, namely (i) straight single-level direct dynamics, (ii) zero-order interpolated variational transition state theory (IVTST-0), (iii) first-order interpolated variational transition state theory (IVTST-1), (iv) interpolated variational transition state theory by mapping (IVTST-M), (v) variational transition state theory with interpolated single-point energies (VTST-ISPE), and (vi) variational transition state theory with interpolated optimized corrections (VTST-IOC). Polyrate can handle multistructural and torsional-potential anharmonicity in conjunction with the MSTor program. Polyrate 2023 contains 112 test runs, and 46 of these are for direct dynamics calculations; 85 of the test runs are single-level runs, and 27 are dual-level calculations.Garcia-Viloca, M; Alhambra, C; Corchado, J; Sánchez, M L; Vill`a, J; Gao, J; Truhlar, D G
CRATE v 9.0.1: Module of CHARMM that Interfaces it to POLYRATE Miscellaneous
2006.
@misc{garciamodule,
title = {CRATE v 9.0.1: Module of CHARMM that Interfaces it to POLYRATE},
author = {M Garcia-Viloca and C Alhambra and J Corchado and M L Sánchez and J Vill{`a} and J Gao and D G Truhlar},
year = {2006},
date = {2006-01-01},
urldate = {2006-01-01},
keywords = {},
pubstate = {published},
tppubtype = {misc}
}
Truhlar, Donald G; Gao, Jiali; Alhambra, Cristobal; Garcia-Viloca, Mireia; Corchado, José; Sánchez, Maria Luz; Villà, Jordi
The incorporation of quantum effects in enzyme kinetics modeling Journal Article
In: Accounts of Chemical Research, vol. 35, no. 6, pp. 341–9, 2002.
@article{Truhlar2002,
title = {The incorporation of quantum effects in enzyme kinetics modeling},
author = {Donald G Truhlar and Jiali Gao and Cristobal Alhambra and Mireia Garcia-Viloca and José Corchado and Maria Luz Sánchez and Jordi Villà},
url = {http://www.ncbi.nlm.nih.gov/pubmed/12069618},
year = {2002},
date = {2002-06-01},
urldate = {2002-06-01},
journal = {Accounts of Chemical Research},
volume = {35},
number = {6},
pages = {341--9},
abstract = {We present an overview of new procedures for including quantum mechanical
effects in enzyme kinetics. Quantum effects are included in three
ways: (1) The electronic structure of the atoms in the catalytic
center is treated quantum mechanically in order to calculate a realistic
potential energy surface for the bond rearrangement process. (2)
The discrete nature of quantum mechanical vibrational energies is
incorporated in the treatment of nuclear motion for computing the
potential of mean force. (3) Multidimensional tunneling contributions
are included. These procedures are illustrated by applications to
proton abstractions catalyzed by enolase and methylamine dehydrogenase
and hydride-transfer reactions by alcohol dehydrogenase and xylose
isomerase.},
keywords = {},
pubstate = {published},
tppubtype = {article}
}
We present an overview of new procedures for including quantum mechanical
effects in enzyme kinetics. Quantum effects are included in three
ways: (1) The electronic structure of the atoms in the catalytic
center is treated quantum mechanically in order to calculate a realistic
potential energy surface for the bond rearrangement process. (2)
The discrete nature of quantum mechanical vibrational energies is
incorporated in the treatment of nuclear motion for computing the
potential of mean force. (3) Multidimensional tunneling contributions
are included. These procedures are illustrated by applications to
proton abstractions catalyzed by enolase and methylamine dehydrogenase
and hydride-transfer reactions by alcohol dehydrogenase and xylose
isomerase.Alhambra, C; Gao, J; Corchado, J C; Villà, J; Truhlar, D G
Quantum Mechanical Dynamical Effects in an Enzyme-Catalyzed Proton Transfer Reaction Journal Article
In: J. Am. Chem. Soc., vol. 121, pp. 2253-2258, 1999.
@article{Alhambra1999,
title = {Quantum Mechanical Dynamical Effects in an Enzyme-Catalyzed Proton Transfer Reaction},
author = {C Alhambra and J Gao and J C Corchado and J Villà and D G Truhlar},
url = {http://pubs.acs.org/doi/abs/10.1021/ja9831655},
year = {1999},
date = {1999-01-01},
urldate = {1999-01-01},
journal = {J. Am. Chem. Soc.},
volume = {121},
pages = {2253-2258},
keywords = {},
pubstate = {published},
tppubtype = {article}
}
Villà, J; Corchado, JC; Gonzalez-Lafont, A; Lluch, JM; Truhlar, DG
In: J. Phys. Chem. A, vol. 103, no. 26, pp. 5061–5074, 1999.
@article{Villa1999,
title = {Variational Transition-State Theory with Optimized Orientation of the Dividing Surface and Semiclassical Tunneling Calculations for Deuterium and Muonium Kinetic Isotope Effects in the Free Radical Association Reaction H + C2H4 -> C2H5},
author = {J Villà and JC Corchado and A Gonzalez-Lafont and JM Lluch and DG Truhlar},
url = {http://pubs.acs.org/doi/abs/10.1021/jp990970c},
year = {1999},
date = {1999-01-01},
urldate = {1999-01-01},
journal = {J. Phys. Chem. A},
volume = {103},
number = {26},
pages = {5061--5074},
keywords = {},
pubstate = {published},
tppubtype = {article}
}
Villà, J; Gonzalez-Lafont, A; Lluch, J M; Truhlar, D G
In: J. Am. Chem. Soc., vol. 120, pp. 5559–5567, 1998.
@article{Villa1998a,
title = {Entropic effects on the dynamical bottleneck location and tunneling contributions for C2H4+H -> C2H5: Variable scaling of external correlation energy for association reactions},
author = {J Villà and A Gonzalez-Lafont and J M Lluch and D G Truhlar},
url = {http://pubs.acs.org/doi/abs/10.1021/ja980131o},
year = {1998},
date = {1998-01-01},
urldate = {1998-01-01},
journal = {J. Am. Chem. Soc.},
volume = {120},
pages = {5559--5567},
keywords = {},
pubstate = {published},
tppubtype = {article}
}
Villà, J; Corchado, J C; Gonzalez-Lafont, A; Lluch, J M; Truhlar, D G
Explanation of deuterium and muonium kinetic isotope effects for a hydrogen atom addition to an olefin Journal Article
In: J. Am. Chem. Soc., vol. 120, pp. 12141–12142, 1998.
@article{Villa1998,
title = {Explanation of deuterium and muonium kinetic isotope effects for a hydrogen atom addition to an olefin},
author = {J Villà and J C Corchado and A Gonzalez-Lafont and J M Lluch and D G Truhlar},
url = {http://pubs.acs.org/doi/abs/10.1021/ja982616i},
year = {1998},
date = {1998-01-01},
urldate = {1998-01-01},
journal = {J. Am. Chem. Soc.},
volume = {120},
pages = {12141--12142},
keywords = {},
pubstate = {published},
tppubtype = {article}
}
Villà--Freixa, J
Universitat Aut`onoma de Barcelona, 1998, ISBN: 9788469203507.
@phdthesis{VillaThesis1998,
title = {Teoria variacional de l'estat de transició: nous desenvolupaments metodol`ogics i la seva aplicació a sistemes d'interès químic},
author = {J Villà--Freixa},
url = {https://tdx.cat/handle/10803/3286#page=1},
isbn = {9788469203507},
year = {1998},
date = {1998-01-01},
urldate = {1998-01-01},
school = {Universitat Aut`onoma de Barcelona},
keywords = {},
pubstate = {published},
tppubtype = {phdthesis}
}
Gonzalez-Lafont, A; Villà, J; Lluch, J M; Bertrán, J; Steckler, R; Truhlar, D G
In: J. Phys. Chem. A, vol. 102, pp. 3420–3428, 1998.
@article{Gonzalez-Lafont1998,
title = {Variational transition state theory and tunneling calculations with reorientation of the generalized transition states for methyl cation transfer},
author = {A Gonzalez-Lafont and J Villà and J M Lluch and J Bertrán and R Steckler and D G Truhlar},
url = {http://pubs.acs.org/doi/abs/10.1021/jp9807672},
year = {1998},
date = {1998-01-01},
urldate = {1998-01-01},
journal = {J. Phys. Chem. A},
volume = {102},
pages = {3420--3428},
keywords = {},
pubstate = {published},
tppubtype = {article}
}
Villà, J; González-Lafont, A; Lluch, J M; Corchado, J C; Espinosa-García, J
In: J. Chem. Phys., pp. 7266-7274, 1997.
@article{Villa1997,
title = {Understanding the activation energy trends for the C$_2$H$_4$ + OH $rightarrow$ C$_2$H$_4$OH reaction by using canonical variational transition state theory},
author = {J Villà and A González-Lafont and J M Lluch and J C Corchado and J Espinosa-García},
url = {http://jcp.aip.org/resource/1/jcpsa6/v107/i18/p7266_s1},
year = {1997},
date = {1997-01-01},
urldate = {1997-01-01},
journal = {J. Chem. Phys.},
pages = {7266-7274},
keywords = {},
pubstate = {published},
tppubtype = {article}
}
Villà, J; Truhlar, D G
Variational Transition State Theory Without the Minimum Energy Path Journal Article
In: Theor. Chem. Acc., vol. 1-4, pp. 317-323, 1997.
@article{Villa1997a,
title = {Variational Transition State Theory Without the Minimum Energy Path},
author = {J Villà and D G Truhlar},
url = {http://www.springerlink.com/content/u14x8t607r6qwmkt/},
year = {1997},
date = {1997-01-01},
urldate = {1997-01-01},
journal = {Theor. Chem. Acc.},
volume = {1-4},
pages = {317-323},
keywords = {},
pubstate = {published},
tppubtype = {article}
}
Villà, J; González-Lafont, A; Lluch, J M
In: J. Phys. Chem., vol. 100, pp. 19389–19397, 1996.
@article{Villa1996,
title = {On kinetic isotope effects as tools to reveal solvation changes accompanying a proton transfer. A canonical unified statistical theory calculation},
author = {J Villà and A González-Lafont and J M Lluch},
url = {http://pubs.acs.org/doi/abs/10.1021/jp9613192},
year = {1996},
date = {1996-01-01},
urldate = {1996-01-01},
journal = {J. Phys. Chem.},
volume = {100},
pages = {19389--19397},
keywords = {},
pubstate = {published},
tppubtype = {article}
}
Villà, J; González-Lafont, A; Lluch, J M; Bertran, J
On the interpolation of the frequencies of vibrational modes in variational transition state calculations: an adiabatic or diabatic scheme? Journal Article
In: Mol. Phys., pp. 633–644, 1996.
@article{Villa1996a,
title = {On the interpolation of the frequencies of vibrational modes in variational transition state calculations: an adiabatic or diabatic scheme?},
author = {J Villà and A González-Lafont and J M Lluch and J Bertran},
url = {http://www.informaworld.com/smpp/content~db=all~content=a713828497},
year = {1996},
date = {1996-01-01},
urldate = {1996-01-01},
journal = {Mol. Phys.},
pages = {633--644},
keywords = {},
pubstate = {published},
tppubtype = {article}
}
- MOLARIS: a computational biochemistry tool for the study of energetics and dynamics of proteins.
Warshel, Arieh; Olsson, Matts H M; Villà-Freixa, Jordi
Computer Simulations of Isotope Effects in Enzyme Catalysis Book Section
In: A., Kohen; H.H., Limbach (Ed.): Isotope effects in chemistry and biology, pp. 621–644, CRC Press, London, 2005.
@incollection{Warshel2005,
title = {Computer Simulations of Isotope Effects in Enzyme Catalysis},
author = {Arieh Warshel and Matts H M Olsson and Jordi Villà-Freixa},
editor = {Kohen A. and Limbach H.H.},
url = {http://www.crcpress.com/product/isbn/9780824724498;jsessionid=+5341thojkuuOlqJyU-LHw**},
year = {2005},
date = {2005-01-01},
urldate = {2005-01-01},
booktitle = {Isotope effects in chemistry and biology},
pages = {621--644},
publisher = {CRC Press},
address = {London},
keywords = {},
pubstate = {published},
tppubtype = {incollection}
}
Chu, Z T; Villà-Freixa, J; Strajbl, M; Schutz, C N; Shurki, A; Warshel, A
MOLARIS version alpha9.06.01 Miscellaneous
2003.
@misc{Chu2003,
title = {MOLARIS version alpha9.06.01},
author = {Z T Chu and J Villà-Freixa and M Strajbl and C N Schutz and A Shurki and A Warshel},
url = {http://futura.usc.edu/programs/index.html},
year = {2003},
date = {2003-01-01},
urldate = {2003-01-01},
publisher = {University of Southern California},
keywords = {},
pubstate = {published},
tppubtype = {misc}
}
Burykin, A; Schutz, C N; `a, Vill J; Warshel, A
Simulations of ion current in realistic models of ion channels: the KcsA potassium channel Journal Article
In: Proteins, vol. 47, no. 3, pp. 265–80, 2002.
@article{Burykin2002,
title = {Simulations of ion current in realistic models of ion channels: the KcsA potassium channel},
author = {A Burykin and C N Schutz and Vill J `a and A Warshel},
url = {http://www.ncbi.nlm.nih.gov/pubmed/11948781},
year = {2002},
date = {2002-05-01},
urldate = {2002-05-01},
journal = {Proteins},
volume = {47},
number = {3},
pages = {265--80},
abstract = {Realistic studies of ion current in biologic channels present a major
challenge for computer simulation approaches. All-atom molecular
dynamics simulations involve serious time limitations that prevent
their use in direct evaluation of ion current in channels with significant
barriers. The alternative use of Brownian dynamics (BD) simulations
can provide the current for simplified macroscopic models. However,
the time needed for accurate calculations of electrostatic energies
can make BD simulations of ion current expensive. The present work
develops an approach that overcomes some of the above challenges
and allows one to simulate ion currents in models of biologic channels.
Our method provides a fast and reliable estimate of the energetics
of the system by combining semimacroscopic calculations of the self-energy
of each ion and an implicit treatment of the interactions between
the ions, as well as the interactions between the ions and the protein-ionizable
groups. This treatment involves the use of the semimacroscopic version
of the protein dipole Langevin dipole (PDLD/S) model in its linear
response approximation (LRA) implementation, which reduces the uncertainties
about the value of the protein "dielectric constant." The resulting
free energy surface is used to generate the forces for on-the-fly
BD simulations of the corresponding ion currents. Our model is examined
in a preliminary simulation of the ion current in the KcsA potassium
channel. The complete free energy profile for a single ion transport
reflects reasonable energetics and captures the effect of the protein-ionized
groups. This calculated profile indicates that we are dealing with
the channel in its closed state. Reducing the barrier at the gate
region allows us to simulate the ion current in a reasonable computational
time. Several limiting cases are examined, including those that reproduce
the observed current, and the nature of the productive trajectories
is considered. The ability to simulate the current in realistic models
of ion channels should provide a powerful tool for studies of the
biologic function of such systems, including the analysis of the
effect of mutations, pH, and electric potentials.},
keywords = {},
pubstate = {published},
tppubtype = {article}
}
Realistic studies of ion current in biologic channels present a major
challenge for computer simulation approaches. All-atom molecular
dynamics simulations involve serious time limitations that prevent
their use in direct evaluation of ion current in channels with significant
barriers. The alternative use of Brownian dynamics (BD) simulations
can provide the current for simplified macroscopic models. However,
the time needed for accurate calculations of electrostatic energies
can make BD simulations of ion current expensive. The present work
develops an approach that overcomes some of the above challenges
and allows one to simulate ion currents in models of biologic channels.
Our method provides a fast and reliable estimate of the energetics
of the system by combining semimacroscopic calculations of the self-energy
of each ion and an implicit treatment of the interactions between
the ions, as well as the interactions between the ions and the protein-ionizable
groups. This treatment involves the use of the semimacroscopic version
of the protein dipole Langevin dipole (PDLD/S) model in its linear
response approximation (LRA) implementation, which reduces the uncertainties
about the value of the protein "dielectric constant." The resulting
free energy surface is used to generate the forces for on-the-fly
BD simulations of the corresponding ion currents. Our model is examined
in a preliminary simulation of the ion current in the KcsA potassium
channel. The complete free energy profile for a single ion transport
reflects reasonable energetics and captures the effect of the protein-ionized
groups. This calculated profile indicates that we are dealing with
the channel in its closed state. Reducing the barrier at the gate
region allows us to simulate the ion current in a reasonable computational
time. Several limiting cases are examined, including those that reproduce
the observed current, and the nature of the productive trajectories
is considered. The ability to simulate the current in realistic models
of ion channels should provide a powerful tool for studies of the
biologic function of such systems, including the analysis of the
effect of mutations, pH, and electric potentials.Shurki, A; Strajbl, M; `a, Vill J; Warshel, A
How much do enzymes really gain by restraining their reacting fragments? Journal Article
In: J Am Chem Soc, vol. 124, no. 15, pp. 4097–107, 2002.
@article{Shurki2002,
title = {How much do enzymes really gain by restraining their reacting fragments?},
author = {A Shurki and M Strajbl and Vill J `a and A Warshel},
url = {http://pubs.acs.org/doi/abs/10.1021/ja012230z},
year = {2002},
date = {2002-04-01},
urldate = {2002-04-01},
journal = {J Am Chem Soc},
volume = {124},
number = {15},
pages = {4097--107},
abstract = {The steric effect, exerted by enzymes on their reacting substrates,
has been considered as a major factor in enzyme catalysis. In particular,
it has been proposed that enzymes catalyze their reactions by pushing
their reacting fragments to a catalytic configuration which is sometimes
called near attack configuration (NAC). This work uses computer simulation
approaches to determine the relative importance of the steric contribution
to enzyme catalysis. The steric proposal is expressed in terms of
well defined thermodynamic cycles that compare the reaction in the
enzyme to the corresponding reaction in water. The S(N)2 reaction
of haloalkane dehalogenase from Xanthobacter autotrophicus GJ10,
which was used in previous studies to support the strain concept
is chosen as a test case for this proposal. The empirical valence
bond (EVB) method provides the reaction potential surfaces in our
studies. The reliability and efficiency of this method make it possible
to obtain stable results for the steric free energy. Two independent
strategies are used to evaluate the actual magnitude of the steric
effect. The first applies restraints on the substrate coordinates
in water in a way that mimics the steric effect of the protein active
site. These restraints are then released and the free energy associated
with the release process provides the desired estimate of the steric
effect. The second approach eliminates the electrostatic interactions
between the substrate and the surrounding in the enzyme and in water,
and compares the corresponding reaction profiles. The difference
between the resulting profiles provides a direct estimate of the
nonelectrostatic contribution to catalysis and the corresponding
steric effect. It is found that the nonelectrostatic contribution
is about -0.7 kcal/mol while the full "apparent steric contribution"
is about -2.2 kcal/mol. The apparent steric effect includes about
-1.5 kcal/mol electrostatic contribution. The total electrostatic
contribution is found to account for almost all the observed catalytic
effect ( approximately -6.1 kcal/mol of the -6.8 calculated total
catalytic effect). Thus, it is concluded that the steric effect is
not the major source of the catalytic power of haloalkane dehalogenase.
Furthermore, it is found that the largest component of the apparent
steric effect is associated with the solvent reorganization energy.
This solvent-induced effect is quite different from the traditional
picture of balance between the repulsive interaction of the reactive
fragments and the steric force of the protein.},
keywords = {},
pubstate = {published},
tppubtype = {article}
}
The steric effect, exerted by enzymes on their reacting substrates,
has been considered as a major factor in enzyme catalysis. In particular,
it has been proposed that enzymes catalyze their reactions by pushing
their reacting fragments to a catalytic configuration which is sometimes
called near attack configuration (NAC). This work uses computer simulation
approaches to determine the relative importance of the steric contribution
to enzyme catalysis. The steric proposal is expressed in terms of
well defined thermodynamic cycles that compare the reaction in the
enzyme to the corresponding reaction in water. The S(N)2 reaction
of haloalkane dehalogenase from Xanthobacter autotrophicus GJ10,
which was used in previous studies to support the strain concept
is chosen as a test case for this proposal. The empirical valence
bond (EVB) method provides the reaction potential surfaces in our
studies. The reliability and efficiency of this method make it possible
to obtain stable results for the steric free energy. Two independent
strategies are used to evaluate the actual magnitude of the steric
effect. The first applies restraints on the substrate coordinates
in water in a way that mimics the steric effect of the protein active
site. These restraints are then released and the free energy associated
with the release process provides the desired estimate of the steric
effect. The second approach eliminates the electrostatic interactions
between the substrate and the surrounding in the enzyme and in water,
and compares the corresponding reaction profiles. The difference
between the resulting profiles provides a direct estimate of the
nonelectrostatic contribution to catalysis and the corresponding
steric effect. It is found that the nonelectrostatic contribution
is about -0.7 kcal/mol while the full "apparent steric contribution"
is about -2.2 kcal/mol. The apparent steric effect includes about
-1.5 kcal/mol electrostatic contribution. The total electrostatic
contribution is found to account for almost all the observed catalytic
effect ( approximately -6.1 kcal/mol of the -6.8 calculated total
catalytic effect). Thus, it is concluded that the steric effect is
not the major source of the catalytic power of haloalkane dehalogenase.
Furthermore, it is found that the largest component of the apparent
steric effect is associated with the solvent reorganization energy.
This solvent-induced effect is quite different from the traditional
picture of balance between the repulsive interaction of the reactive
fragments and the steric force of the protein.Villà, J; Warshel, A
Modeling and analyzing biocatalysis Book Section
In: Encyclopedia of Catalysis, Wiley Interscience, 2002.
@incollection{Villa2002,
title = {Modeling and analyzing biocatalysis},
author = {J Villà and A Warshel},
url = {http://mrw.interscience.wiley.com/emrw/9780471227618/enccat/article/eoc048/current/abstract},
doi = {10.1002/0471227617.eoc048},
year = {2002},
date = {2002-01-01},
urldate = {2002-01-01},
booktitle = {Encyclopedia of Catalysis},
publisher = {Wiley Interscience},
keywords = {},
pubstate = {published},
tppubtype = {incollection}
}
Warshel, A; Florián, J; Strajbl, M; Vill`a, J
Circe effect versus enzyme preorganization: what can be learned from the structure of the most proficient enzyme? Journal Article
In: Chembiochem, vol. 2, no. 2, pp. 109–111, 2001.
@article{Warshel_2001_109,
title = {Circe effect versus enzyme preorganization: what can be learned from the structure of the most proficient enzyme?},
author = {A Warshel and J Florián and M Strajbl and J Vill{`a}},
year = {2001},
date = {2001-02-01},
urldate = {2001-02-01},
journal = {Chembiochem},
volume = {2},
number = {2},
pages = {109--111},
institution = {Department of Chemistry, University of Southern California, 3620 McClintock Av. SGM #418, Los Angeles, CA 90089-1062, USA. warshel@usc.edu},
keywords = {},
pubstate = {published},
tppubtype = {article}
}
Villà, J; Warshel, A
Energetics and Dynamics of Enzymatic Reactions Journal Article
In: J. Phys. Chem. B, vol. 105, pp. 7887–907, 2001.
@article{Villa2001,
title = {Energetics and Dynamics of Enzymatic Reactions},
author = {J Villà and A Warshel},
url = {http://pubs.acs.org/doi/abs/10.1021/jp011048h},
year = {2001},
date = {2001-01-01},
urldate = {2001-01-01},
journal = {J. Phys. Chem. B},
volume = {105},
pages = {7887--907},
keywords = {},
pubstate = {published},
tppubtype = {article}
}
Warshel, A; Strajbl, M; `a, Vill J; á, Flori J
In: Biochemistry, vol. 39, no. 48, pp. 14728–38, 2000.
@article{Warshel2000,
title = {Remarkable rate enhancement of orotidine 5'-monophosphate decarboxylase is due to transition-state stabilization rather than to ground-state destabilization},
author = {A Warshel and M Strajbl and Vill J `a and Flori J á},
url = {http://www.ncbi.nlm.nih.gov/pubmed/11101287},
year = {2000},
date = {2000-12-01},
urldate = {2000-12-01},
journal = {Biochemistry},
volume = {39},
number = {48},
pages = {14728--38},
abstract = {The remarkable rate enhancement of orotidine 5'-phosphate decarboxylase
(ODCase) has been attributed to ground-state destabilization (GSD)
by desolvation and more recently to GSD by electrostatic stress.
Here we reiterate our previous arguments that the GSD mechanisms
are not likely to play a major role in enzyme catalysis and analyze
quantitatively the origin of the rate enhancement of ODCase. This
analysis involves energy considerations and computer simulations.
Our energy considerations show that (i) the previously proposed desolvation
mechanism is based on an improper reference state; (ii) a nonpolar
active site cannot account for the catalytic effect of the enzyme;
(iii) the focus on the role of the negatively charged protein residues
in the electrostatic stress GSD mechanism overlooks the fact that
the positively charged Lys72 strongly stabilizes the substrate; (iv)
although the previous calculation of the actual enzymatic reaction
correctly reproduced the observed rate enhancement, it could not
obtain this rate enhancement from the calculated binding energies
(which are the relevant quantities for determining GSD effects);
(v) the GSD mechanism is inconsistent with the observed binding energy
of the phosphoribosyl part of the substrate; and (vi) the presumably
unstable substrate (orotate) can be stabilized, at equilibrium, by
accepting a proton from the solvent. Our computer simulation studies
involve two set of calculations. First, we study the catalytic reaction
by using an empirical valence bond potential surface calibrated by
ab initio calculations of the reference solution reaction. This calculation
reproduces the observed catalytic effect of the enzyme. Next, we
use free-energy perturbation calculations and evaluated the electrostatic
contributions to the binding energies of the ground state and transition
state (TS). These calculations show that the rate enhancement in
ODCase is due to the TS stabilization rather than to GSD. The differences
between our own and the previous theoretical analyses stem from both
the selection of the reacting system and the treatment of the long-range
electrostatic contributions to the binding energy. The reacting system
was previously assumed to encompass only the orotate. However, this
selection does not allow proper description of the reaction catalyzed
by the enzyme (i.e., [Orotate(-) + LysH(+)] if [uracil + Lys + CO(2)]).
Therefore, the reacting system should include both orotate and the
general acid in the form of the protonated Lys72 protein residue.
This selection leads to a simple and consistent interpretation of
the catalytic effect where the electrostatic stabilization of the
transition state is due to the fact that the two negatively charged
aspartic residues are already placed near the reactive lysine so
that they do not have to reorganize significantly during the reaction.
Interestingly, even calculations with only orotate(-) as the reacting
system do not produce sufficient destabilization to account for a
GSD mechanism. In summary, we conclude, in agreement with previous
workers, that ODCase catalyzes its reaction by electrostatic effects.
However, we show that these effects are associated with TS stabilization
due to a reduction in the protein-protein reorganization energy and
not with protein-substrate destabilization effects.},
keywords = {},
pubstate = {published},
tppubtype = {article}
}
The remarkable rate enhancement of orotidine 5'-phosphate decarboxylase
(ODCase) has been attributed to ground-state destabilization (GSD)
by desolvation and more recently to GSD by electrostatic stress.
Here we reiterate our previous arguments that the GSD mechanisms
are not likely to play a major role in enzyme catalysis and analyze
quantitatively the origin of the rate enhancement of ODCase. This
analysis involves energy considerations and computer simulations.
Our energy considerations show that (i) the previously proposed desolvation
mechanism is based on an improper reference state; (ii) a nonpolar
active site cannot account for the catalytic effect of the enzyme;
(iii) the focus on the role of the negatively charged protein residues
in the electrostatic stress GSD mechanism overlooks the fact that
the positively charged Lys72 strongly stabilizes the substrate; (iv)
although the previous calculation of the actual enzymatic reaction
correctly reproduced the observed rate enhancement, it could not
obtain this rate enhancement from the calculated binding energies
(which are the relevant quantities for determining GSD effects);
(v) the GSD mechanism is inconsistent with the observed binding energy
of the phosphoribosyl part of the substrate; and (vi) the presumably
unstable substrate (orotate) can be stabilized, at equilibrium, by
accepting a proton from the solvent. Our computer simulation studies
involve two set of calculations. First, we study the catalytic reaction
by using an empirical valence bond potential surface calibrated by
ab initio calculations of the reference solution reaction. This calculation
reproduces the observed catalytic effect of the enzyme. Next, we
use free-energy perturbation calculations and evaluated the electrostatic
contributions to the binding energies of the ground state and transition
state (TS). These calculations show that the rate enhancement in
ODCase is due to the TS stabilization rather than to GSD. The differences
between our own and the previous theoretical analyses stem from both
the selection of the reacting system and the treatment of the long-range
electrostatic contributions to the binding energy. The reacting system
was previously assumed to encompass only the orotate. However, this
selection does not allow proper description of the reaction catalyzed
by the enzyme (i.e., [Orotate(-) + LysH(+)] if [uracil + Lys + CO(2)]).
Therefore, the reacting system should include both orotate and the
general acid in the form of the protonated Lys72 protein residue.
This selection leads to a simple and consistent interpretation of
the catalytic effect where the electrostatic stabilization of the
transition state is due to the fact that the two negatively charged
aspartic residues are already placed near the reactive lysine so
that they do not have to reorganize significantly during the reaction.
Interestingly, even calculations with only orotate(-) as the reacting
system do not produce sufficient destabilization to account for a
GSD mechanism. In summary, we conclude, in agreement with previous
workers, that ODCase catalyzes its reaction by electrostatic effects.
However, we show that these effects are associated with TS stabilization
due to a reduction in the protein-protein reorganization energy and
not with protein-substrate destabilization effects.Villà, J; Strajbl, M; Glennon, T M; Sham, Y Y; Chu, Z T; Warshel, A
How important are entropic contributions to enzyme catalysis? Journal Article
In: Proc. Natl. Acad. Sci. USA, vol. 97, no. 22, pp. 11899–904, 2000.
@article{Villa2000b,
title = {How important are entropic contributions to enzyme catalysis?},
author = {J Villà and M Strajbl and T M Glennon and Y Y Sham and Z T Chu and A Warshel},
url = {http://www.pnas.org/content/97/22/11899.abstract},
doi = {10.1073/pnas.97.22.11899},
year = {2000},
date = {2000-10-01},
urldate = {2000-10-01},
journal = {Proc. Natl. Acad. Sci. USA},
volume = {97},
number = {22},
pages = {11899--904},
abstract = {The idea that enzymes accelerate their reactions by entropic effects
has played a major role in many prominent proposals about the origin
of enzyme catalysis. This idea implies that the binding to an enzyme
active site freezes the motion of the reacting fragments and eliminates
their entropic contributions, (delta S(cat)(double dagger))', to
the activation energy. It is also implied that the binding entropy
is equal to the activation entropy, (delta S(w)(double dagger))',
of the corresponding solution reaction. It is, however, difficult
to examine this idea by experimental approaches. The present paper
defines the entropic proposal in a rigorous way and develops a computer
simulation approach that determines (delta S(double dagger))'. This
approach allows us to evaluate the differences between (delta S(double
dagger))' of an enzymatic reaction and of the corresponding reference
reaction in solution. Our approach is used in a study of the entropic
contribution to the catalytic reaction of subtilisin. It is found
that this contribution is much smaller than previously thought. This
result is due to the following: (i) Many of the motions that are
free in the reactants state of the reference solution reaction are
also free at the transition state. (ii) The binding to the enzyme
does not completely freeze the motion of the reacting fragments so
that (delta S(double dagger))' in the enzymes is not zero. (iii)
The binding entropy is not necessarily equal to (delta S(w)(double
dagger))'.},
keywords = {},
pubstate = {published},
tppubtype = {article}
}
The idea that enzymes accelerate their reactions by entropic effects
has played a major role in many prominent proposals about the origin
of enzyme catalysis. This idea implies that the binding to an enzyme
active site freezes the motion of the reacting fragments and eliminates
their entropic contributions, (delta S(cat)(double dagger))', to
the activation energy. It is also implied that the binding entropy
is equal to the activation entropy, (delta S(w)(double dagger))',
of the corresponding solution reaction. It is, however, difficult
to examine this idea by experimental approaches. The present paper
defines the entropic proposal in a rigorous way and develops a computer
simulation approach that determines (delta S(double dagger))'. This
approach allows us to evaluate the differences between (delta S(double
dagger))' of an enzymatic reaction and of the corresponding reference
reaction in solution. Our approach is used in a study of the entropic
contribution to the catalytic reaction of subtilisin. It is found
that this contribution is much smaller than previously thought. This
result is due to the following: (i) Many of the motions that are
free in the reactants state of the reference solution reaction are
also free at the transition state. (ii) The binding to the enzyme
does not completely freeze the motion of the reacting fragments so
that (delta S(double dagger))' in the enzymes is not zero. (iii)
The binding entropy is not necessarily equal to (delta S(w)(double
dagger))'.Glennon, T M; `a, Vill J; Warshel, A
How does GAP catalyze the GTPase reaction of Ras? A computer simulation study Journal Article
In: Biochemistry, vol. 39, no. 32, pp. 9641–51, 2000.
@article{Glennon2000,
title = {How does GAP catalyze the GTPase reaction of Ras? A computer simulation study},
author = {T M Glennon and Vill J `a and A Warshel},
url = {http://pubs.acs.org/doi/abs/10.1021/bi000640e},
year = {2000},
date = {2000-08-01},
urldate = {2000-08-01},
journal = {Biochemistry},
volume = {39},
number = {32},
pages = {9641--51},
abstract = {The formation of a complex between p21(ras) and GAP accelerates the
GTPase reaction of p21(ras) and terminates the signal for cell proliferation.
The understanding of this rate acceleration is important for the
elucidation of the role of Ras mutants in tumor formation. In principle
there are two main options for the origin of the effect of GAP. One
is a direct electrostatic interaction between the residues of GAP
and the transition state of the Ras-GAP complex and the other is
a GAP-induced shift of the structure of Ras to a configuration that
increases the stabilization of the transition state. This work examines
the relative importance of these options by computer simulations
of the catalytic effect of Ras. The simulations use the empirical
valence bond (EVB) method to study the GTPase reaction along the
alternative associative and dissociative paths. This approach reproduces
the trend in the overall experimentally observed catalytic effect
of GAP: the calculated effect is 7 +/- 3 kcal/mol as compared to
the observed effect of approximately 6.6 kcal/mol. Furthermore, the
calculated effect of mutating Arg789 to a nonpolar residue is 3-4
kcal/mol as compared to the observed effect of 4.5 kcal/mol for the
Arg789Ala mutation. It is concluded, in agreement with previous proposals,
that the effect of Arg789 is associated with its direct interaction
with the transition state charge distribution. However, calculations
that use the coordinates of Ras from the Ras-GAP complex (referred
to here as Ras') reproduce a significant catalytic effect relative
to the Ras coordinates. This indicates that part of the effect of
GAP involves a stabilization of a catalytic configuration of Ras.
This configuration increases the positive electrostatic potential
on the beta-phosphate (relative to the corresponding situation in
the free Ras). In other words, GAP stabilizes the GDP bound configuration
of Ras relative to that of the GTP-bound conformation. The elusive
oncogenic effect of mutating Gln61 is also explored. The calculated
effect of such mutations in the Ras-GAP complex are found to be small,
while the observed effect is very large (8.7 kcal/mol). Since the
Ras is locked in its Ras-GAP configuration in our simulations, we
conclude that the oncogenic effect of mutation of Gln61 is indirect
and is associated most probably with the structural changes of Ras
upon forming the Ras-GAP complex. In view of these and the results
for the Ras' we conclude that GAP activates Ras by both direct electrostatic
stabilization of the transition state and an indirect allosteric
effect that stabilizes the GDP-bound form. The present study also
explored the feasibility of the associative and dissociative mechanism
in the GTPase reaction of Ras. It is concluded that the reaction
is most likely to involve an associative mechanism.},
keywords = {},
pubstate = {published},
tppubtype = {article}
}
The formation of a complex between p21(ras) and GAP accelerates the
GTPase reaction of p21(ras) and terminates the signal for cell proliferation.
The understanding of this rate acceleration is important for the
elucidation of the role of Ras mutants in tumor formation. In principle
there are two main options for the origin of the effect of GAP. One
is a direct electrostatic interaction between the residues of GAP
and the transition state of the Ras-GAP complex and the other is
a GAP-induced shift of the structure of Ras to a configuration that
increases the stabilization of the transition state. This work examines
the relative importance of these options by computer simulations
of the catalytic effect of Ras. The simulations use the empirical
valence bond (EVB) method to study the GTPase reaction along the
alternative associative and dissociative paths. This approach reproduces
the trend in the overall experimentally observed catalytic effect
of GAP: the calculated effect is 7 +/- 3 kcal/mol as compared to
the observed effect of approximately 6.6 kcal/mol. Furthermore, the
calculated effect of mutating Arg789 to a nonpolar residue is 3-4
kcal/mol as compared to the observed effect of 4.5 kcal/mol for the
Arg789Ala mutation. It is concluded, in agreement with previous proposals,
that the effect of Arg789 is associated with its direct interaction
with the transition state charge distribution. However, calculations
that use the coordinates of Ras from the Ras-GAP complex (referred
to here as Ras') reproduce a significant catalytic effect relative
to the Ras coordinates. This indicates that part of the effect of
GAP involves a stabilization of a catalytic configuration of Ras.
This configuration increases the positive electrostatic potential
on the beta-phosphate (relative to the corresponding situation in
the free Ras). In other words, GAP stabilizes the GDP bound configuration
of Ras relative to that of the GTP-bound conformation. The elusive
oncogenic effect of mutating Gln61 is also explored. The calculated
effect of such mutations in the Ras-GAP complex are found to be small,
while the observed effect is very large (8.7 kcal/mol). Since the
Ras is locked in its Ras-GAP configuration in our simulations, we
conclude that the oncogenic effect of mutation of Gln61 is indirect
and is associated most probably with the structural changes of Ras
upon forming the Ras-GAP complex. In view of these and the results
for the Ras' we conclude that GAP activates Ras by both direct electrostatic
stabilization of the transition state and an indirect allosteric
effect that stabilizes the GDP-bound form. The present study also
explored the feasibility of the associative and dissociative mechanism
in the GTPase reaction of Ras. It is concluded that the reaction
is most likely to involve an associative mechanism.Villà, J; Bentzien, J; González-Lafont, A; Lluch, J M; Bertran, J; Warshel, A
In: J. Comp. Chem., vol. 21, pp. 607-625, 2000.
@article{Villa2000a,
title = {An Effective Way of Modelling Chemical Catalysis: An Empirical Valence Bond Picture of the Role of the Solvent and Catalyst in Alkylation Reactions},
author = {J Villà and J Bentzien and A González-Lafont and J M Lluch and J Bertran and A Warshel},
url = {http://onlinelibrary.wiley.com/doi/10.1002/(SICI)1096-987X(200006)21:8%3C607::AID-JCC3%3E3.0.CO;2-R/pdf},
year = {2000},
date = {2000-01-01},
urldate = {2000-01-01},
journal = {J. Comp. Chem.},
volume = {21},
pages = {607-625},
keywords = {},
pubstate = {published},
tppubtype = {article}
}
Strajbl, M; Sham, Y Y; Villà, J; Chu, Z T; Warshel, A
Calculations of Activation Entropies of Chemical Reactions in Solution Journal Article
In: J. Phys. Chem. B, vol. 104, pp. 4578 -4584, 2000.
@article{vStrajbl2000a,
title = {Calculations of Activation Entropies of Chemical Reactions in Solution},
author = {M Strajbl and Y Y Sham and J Villà and Z T Chu and A Warshel},
url = {http://pubs.acs.org/doi/abs/10.1021/jp0003095},
year = {2000},
date = {2000-01-01},
urldate = {2000-01-01},
journal = {J. Phys. Chem. B},
volume = {104},
pages = {4578 -4584},
keywords = {},
pubstate = {published},
tppubtype = {article}
}