Publications

@article{Bartrons2025,

title = {Why ponds concentrate nutrients: the roles of internal features, land use, and climate},

author = {Mireia Bartrons and Jing Yang and Maria Cuenca-Cambronero and Pieter Lemmens and Maria Anton-Pardo and Meryem Beklioğlu and Jeremy Biggs and Aurélie Boissezon and Dani Boix and Clementina Calvo and Maite Colina and Thomas A. Davidson and Luc De Meester and Julie C. Fahy and Helen M. Greaves and Hilal Kiran and Eti E. Levi and Thomas Mehner and Mariana Meerhoff and Emine B. Mülayim and Ian Patmore and Carl D. Sayer and Jordi Villà-Freixa and Sandra Brucet

},

url = {https://mon.uvic.cat/cbbl/new-article-on-data-analysis-of-freshwater-ponds-nutrients-in-response-to-environmental-variables/},

doi = {10.1007/s10750-025-05907-0},

year  = {2025},

date = {2025-12-31},

urldate = {2025-12-31},

journal = {Hydrobiologia},

abstract = {Ponds are key freshwater habitats sup-

porting biodiversity and ecosystem services, yet they

remain understudied in the context of land use and

climate change. We examined 240 ponds across eight

countries (seven in Europe and Uruguay) to assess

how internal pond characteristics, surrounding land

cover and livestock intensity, seasonal climatic vari-

ation, and climate influence nutrient concentrations

across spatial and temporal scales. Nutrient concen-

trations were strongly associated with internal fea-

tures: shallow ponds and short hydroperiods had

higher total nitrogen (TN) and total phosphorus (TP)

concentrations, while thermal stratification, typically

found in deeper ponds, was associated with higher

TN, indicating enhanced internal nutrient recycling.

Land use also played a significant role with agricul-

tural intensity increasing nutrient concentration (both

TN and TP), whereas forest cover reduced TP. Sea-

sonal variation modulated these patterns, with higher

TP concentrations observed in summer, and with

dilution effects during wetter and cooler periods, par-

ticularly for TN in semi-permanent ponds. These find-

ings underscore the combined influence of physical

characteristics, landscape context, and climate vari-

ability on nutrient concentrations },

keywords = {ecology, nutrients, ponds, R, statistical inference},

pubstate = {published},

tppubtype = {article}

}

@article{Badia-i-Mompel2025,

title = {Comparison and evaluation of methods to infer gene regulatory networks from multimodal single-cell data},

author = {Pau Badia-i-Mompel and *Roger Casals-Franch* and Lorna Wessels and Sophia Müller-Dott and Rémi Trimbour and Yunxiao Yang and Ricardo O. Ramirez Flores and Julio Saez-Rodriguez},

url = {https://mon.uvic.cat/cbbl/2629-2/},

doi = {https://doi.org/10.1101/2024.12.20.629764 },

year  = {2025},

date = {2025-12-31},

urldate = {2025-12-31},

journal = {bioRxiv},

abstract = {Cells regulate their functions through gene expression, driven by a complex interplay of transcription factors and other regulatory mechanisms that together can be modeled as gene regulatory networks (GRNs). The emergence of single-cell multi-omics technologies has driven the development of several methods that integrate transcriptomics and chromatin accessibility data to infer GRNs. While these methods provide examples of their utility in discovering new regulatory interactions, a comprehensive benchmark evaluating their mechanistic and predictive properties as well as their ability to recover known interactions is lacking. To address this, we built a comprehensive framework, Gene Regulatory nETwork Analysis (GRETA), available as a Snakemake pipeline, that includes state of the art methods decomposing their different steps in a modular manner. With it, we found that the GRNs were highly sensitive to methods’ choices, such as changes in random seeds, or replacing steps in the inference pipelines, as well as whether they use paired or unpaired multimodal data. Although the obtained networks performed moderately well in predictive evaluation tasks and partially recovered known interactions, they struggled to capture causal relationships from perturbation assays. Our work brings attention to the challenges of inferring GRNs from single-cell omics, offers guidelines, and presents a flexible framework for developing and testing new approaches.},

keywords = {gene regulatory networks, modeling, single cell, transcriptomics},

pubstate = {published},

tppubtype = {article}

}

@article{Alemany-Fornés2025,

title = {Trehalose mediated stabilisation of diamine oxidase (DAO)-rich supplements from pea sprouts in industrial manufacturing},

author = {Marc Alemany-Fornés and Pau Domínguez-Sorribas and Jordi Villà-Freixa and Jaume Bori and Enrique Calvo and Manuel Suárez and Begoña Muguerza},

year  = {2025},

date = {2025-12-31},

urldate = {2025-12-31},

journal = {submitted},

keywords = {AMBER, diamine oxidase, Electrostatics, glucosides, Molecular Dynamics, Molecular Modeling},

pubstate = {published},

tppubtype = {article}

}

@article{Álvarez-Villanueva2023,

title = {Separation-of-function mutants reveal the NF-κB-independent involvement of IκBα in the regulation of stem cell and oncogenic programs},

author = {Daniel Álvarez-Villanueva and Luis Galán-Palma and Joan Bertran and Martin Floor and Laura Solé and Teresa Lobo-Jarne and María Maqueda and Rajani Rajbhandari and Laura Marruecos and Jordi Villà-Freixa and Markus Bredel and Anna Bigas and Lluís Espinosa},

url = {https://www.biorxiv.org/content/10.1101/2023.06.21.545928v1.abstract},

doi = {10.1101/2023.06.21.545928},

year  = {2025},

date = {2025-06-11},

journal = {Cell Reports},

volume = {accepted},

abstract = {We previously demonstrated that the NF-κB inhibitor IκBα binds the chromatin together with PRC2 to regulate a subset of developmental- and stem cell-related genes. This alternative function has been elusive in both physiological and disease conditions because of the predominant role of IκBα as a negative regulator of NF-κB.



We here uniquely characterize specific residues of IκBα that allow the generation of separation-of-function (SOF) mutants that are defective for either NF-κB-related (SOFΔNF-κB) or chromatin-related (SOFΔH2A,H4) activities. Expression of IκBα SOFΔNF-κB, but not SOFΔH2A/H4, is sufficient to negatively regulate a specific stemness program in intestinal cells, thus rescuing the differentiation blockage imposed by IκBα deficiency. In contrast, full IκBα activity is required for regulating clonogenic/tumor-initiating activity of colorectal cancer cells.



Our data indicate that SOF mutants represent an exclusive tool for studying IκBα functions in physiology and disease, and identified IκBα as a robust prognosis biomarker for human cancer.},

keywords = {Electrostatics, Free energy calculations, Histones, Molecular Dynamics, NF-KB, Protein protein interactions},

pubstate = {published},

tppubtype = {article}

}

@article{Rees2024,

title = {Ancient Loss of Catalytic Selenocysteine Spurred Convergent Adaptation in a Mammalian Oxidoreductase},

author = {Jasmin Rees and Gaurab Sarangi and Qing Cheng and Martin Floor and Aida M Andrés and Baldomero Oliva Miguel and Jordi Villà-Freixa and Elias S J Arnér and Sergi Castellano},

url = {https://academic.oup.com/gbe/article/16/3/evae041/7623291},

doi = {10.1093/gbe/evae041},

year  = {2024},

date = {2024-03-01},

urldate = {2024-03-01},

journal = {Genome Biology and Evolution},

volume = {16},

issue = {3},

pages = {evae041},

abstract = {Selenocysteine, the 21st amino acid specified by the genetic code, is a rare selenium-containing residue found in the catalytic site of selenoprotein oxidoreductases. Selenocysteine is analogous to the common cysteine amino acid, but its selenium atom offers physical–chemical properties not provided by the corresponding sulfur atom in cysteine. Catalytic sites with selenocysteine in selenoproteins of vertebrates are under strong purifying selection, but one enzyme, glutathione peroxidase 6 (GPX6), independently exchanged selenocysteine for cysteine <100 million years ago in several mammalian lineages. We reconstructed and assayed these ancient enzymes before and after selenocysteine was lost and up to today and found them to have lost their classic ability to reduce hydroperoxides using glutathione. This loss of function, however, was accompanied by additional amino acid changes in the catalytic domain, with protein sites concertedly changing under positive selection across distant lineages abandoning selenocysteine in glutathione peroxidase 6. This demonstrates a narrow evolutionary range in maintaining fitness when sulfur in cysteine impairs the catalytic activity of this protein, with pleiotropy and epistasis likely driving the observed convergent evolution. We propose that the mutations shared across distinct lineages may trigger enzymatic properties beyond those in classic glutathione peroxidases, rather than simply recovering catalytic rate. These findings are an unusual example of adaptive convergence across mammalian selenoproteins, with the evolutionary signatures possibly representing the evolution of novel oxidoreductase functions.},

keywords = {chemistry; Enzymes, Enzyme Activation, evolution, Molecular Dynamics, Molecular Modeling, selenoproteins},

pubstate = {published},

tppubtype = {article}

}

@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 = {atmospheric chemistry, chemical dynamics, POLYRATE, Quantum Theory, transition state theory},

pubstate = {published},

tppubtype = {article}

}

@article{nokey,

title = {Identification of Aggregation Mechanism of Acetylated PHF6* and PHF6 Tau Peptides Based on Molecular Dynamics Simulations and Markov State Modeling},

author = {Syed Jawad Ali Shah and Qianqian Zhang and Jingjing Guo and Hongli Liu and Huanxiang Liu and and Jordi Villà-Freixa},

url = {https://pubs.acs.org/doi/abs/10.1021/acschemneuro.3c00578},

doi = {10.1021/acschemneuro.3c00578},

year  = {2023},

date = {2023-10-13},

urldate = {2023-10-13},

journal = {ACS Chem. Neurosci.},

volume = {14},

issue = {21},

pages = {3959-3971},

abstract = {The microtubule-associated protein tau (MAPT) has a critical role in the development and preservation of the nervous system. However, tau’s dysfunction and accumulation in the human brain can lead to several neurodegenerative diseases, such as Alzheimer’s disease, Down’s syndrome, and frontotemporal dementia. The microtubule binding (MTB) domain plays a significant, important role in determining the tau’s pathophysiology, as the core of paired helical filaments PHF6* (275VQIINK280) and PHF6 (306VQIVYK311) of R2 and R3 repeat units, respectively, are formed in this region, which promotes tau aggregation. Post-translational modifications, and in particular lysine acetylation at K280 of PHF6* and K311 of PHF6, have been previously established to promote tau misfolding and aggregation. However, the exact aggregation mechanism is not known. In this study, we established an atomic-level nucleation-extension mechanism of the separated aggregation of acetylated PHF6* and PHF6 hexapeptides, respectively, of tau. We show that the acetylation of the lysine residues promotes the formation of β-sheet enriched high-ordered oligomers. The Markov state model analysis of ac-PHF6* and ac-PHF6 aggregation revealed the formation of an antiparallel dimer nucleus which could be extended from both sides in a parallel manner to form mixed-oriented and high-ordered oligomers. Our study describes the detailed mechanism for acetylation-driven tau aggregation, which provides valuable insights into the effect of post-translation modification in altering the pathophysiology of tau hexapeptides.},

keywords = {Alzheimer disease, chemistry; Protein Conformation, Molecular Dynamics, tau},

pubstate = {published},

tppubtype = {article}

}

@article{Quandt2023,

title = {CDK6 is activated by the atypical cyclin I to promote E2F-mediated gene expression and cancer cell proliferation},

author = {Eva Quandt and Núria Masip and Sara Hernández-Ortega and Abril Sánchez-Botet and Laura Gasa and Ainhoa Fernández-Elorduy and Sara Plutta and Joan Marc Martínez-Laínez and Samuel Bru and Pau M. Muñoz-Torres and Martin Floor and Jordi Villà-Freixa and May C. Morris and August Vidal and Alberto Villanueva and Josep Clotet and Mariana P.C. Ribeiro},

url = {https://febs.onlinelibrary.wiley.com/doi/full/10.1002/1878-0261.13438},

doi = {10.1002/1878-0261.13438},

year  = {2023},

date = {2023-04-20},

urldate = {2023-04-20},

journal = {Molecular Oncology},

volume = {17},

issue = {7},

pages = {1228-1245},

abstract = {Cyclin-dependent kinases (CDKs), together with their cyclin partners, are the master cell cycle regulators. Remarkably, the cyclin family was extended to include atypical cyclins, characterized by distinctive structural features, but their partner CDKs remain elusive. Here, we conducted a yeast two-hybrid screen to identify new atypical cyclin–CDK complexes. We identified 10 new complexes, including a complex between CDK6 and cyclin I (CCNI), which was found to be active against retinoblastoma protein. CCNI upregulation increased the proliferation of breast cancer cells in vitro and in vivo, with a magnitude similar to that seen upon cyclin D upregulation, an effect that was abrogated by CDK6 silencing or palbociclib treatment. In line with these findings, CCNI downregulation led to a decrease in cell number and a reduction in the percentage of cells reaching S phase. Finally, CCNI upregulation correlated with the high expression of E2F target genes in large panels of cancer cell lines and tissue samples from breast cancer patients. In conclusion, we unveil CCNI as a new player in the pathways that activate CDK6, enriching the wiring of cell cycle control.},

keywords = {chemistry; Cyclins, Electrostatics, Molecular Dynamics, Molecular Modeling, Protein protein interactions},

pubstate = {published},

tppubtype = {article}

}

@article{Hernández2021,

title = {New mutations in HFE2 and TFR2 genes causing Non HFE-related  Hereditary Hemochromatosis},

author = {Hernández, Gonzalo and Ferrer-Cortès, Xenia and Venturi, Veronica and Musri, Melina and Pilquil, Martin Floor and Torres, Pau Marc Muñoz and Rodríguez, Ines Hernandez and Mínguez, Maria Àngels Ruiz and Kelleher, Nicholas J. and Pelucchi, Sara and Piperno, Alberto and Alberca, Esther Plensa and Ricós, Georgina Gener and Giró, Eloi Cañamero and Pérez-Montero, Santiago and Tornador, Cristian and Villà-Freixa, Jordi and Sánchez, Mayka},

url = {https://www.mdpi.com/2073-4425/12/12/1980},

doi = {10.3390/genes12121980},

issn = {2073-4425},

year  = {2021},

date = {2021-12-12},

urldate = {2021-12-12},

journal = {Genes},

volume = {12},

number = {12},

pages = {1980'},

abstract = {Hereditary hemochromatosis (HH) is an iron metabolism disease clinically characterized by excessive iron deposition in parenchymal organs such as liver, heart, pancreas, and joints. It is caused by mutations in at least five different genes. HFE hemochromatosis is the most common type of hemochromatosis, while non-HFE related hemochromatosis are rare cases. Here, we describe six new patients of non-HFE related HH from five different families. Two families (Family 1 and 2) have novel nonsense mutations in the HFE2 gene have novel nonsense mutations (p.Arg63Ter and Asp36ThrfsTer96). Three families have mutations in the TFR2 gene, one case has one previously unreported mutation (Family A—p.Asp680Tyr) and two cases have known pathogenic mutations (Family B and D—p.Trp781Ter and p.Gln672Ter respectively). Clinical, biochemical, and genetic data are discussed in all these cases. These rare cases of non-HFE related hereditary hemochromatosis highlight the importance of an earlier molecular diagnosis in a specialized center to prevent serious clinical complications.},

keywords = {Electrostatics, Molecular Dynamics, Molecular Modeling, Protein protein interactions, Rosetta},

pubstate = {published},

tppubtype = {article}

}

@article{Marruecos2021,

title = {Dynamic chromatin association of IκBα is regulated by acetylation and cleavage of histone H4},

author = {Laura Marruecos and Joan Bertran and Daniel Álvarez-Villanueva and María Carmen Mulero and Yolanda Guillén and Luis G Palma and Martin Floor and Anna Vert and Sara Arce-Gallego and Irene Pecharroman and Laura Batlle and Jordi Villà-Freixa and Gourisankar Ghosh and Anna Bigas and Lluís Espinosa},

url = {https://pubmed.ncbi.nlm.nih.gov/34224210/},

doi = {10.15252/embr.202152649},

issn = {1469-3178},

year  = {2021},

date = {2021-08-04},

urldate = {2021-08-04},

journal = {EMBO Reports},

number = {e52649},

abstract = {IκBs exert principal functions as cytoplasmic inhibitors of NF-kB transcription factors. Additional roles for IκB homologues have been described, including chromatin association and transcriptional regulation. Phosphorylated and SUMOylated IκBα (pS-IκBα) binds to histones H2A and H4 in the stem cell and progenitor cell compartment of skin and intestine, but the mechanisms controlling its recruitment to chromatin are largely unknown. Here, we show that serine 32-36 phosphorylation of IκBα favors its binding to nucleosomes and demonstrate that p-IκBα association with H4 depends on the acetylation of specific H4 lysine residues. The N-terminal tail of H4 is removed during intestinal cell differentiation by proteolytic cleavage by trypsin or chymotrypsin at residues 17-19, which reduces p-IκBα binding. Inhibition of trypsin and chymotrypsin activity in HT29 cells increases p-IκBα chromatin binding but, paradoxically, impaired goblet cell differentiation, comparable to IκBα deletion. Taken together, our results indicate that dynamic binding of IκBα to chromatin is a requirement for intestinal cell differentiation and provide a molecular basis for the understanding of the restricted nuclear distribution of p-IκBα in specific stem cell compartments.},

keywords = {chemistry; Animals; Binding Sites; Computational Biology, chemistry/metabolism; Point Mutation; Protein Binding; RING Finger Domains; Simulation; Static Electricity; Ubiquitin-Conjugating Enzymes},

pubstate = {published},

tppubtype = {article}

}

@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 = {Computer code, Markov models, Molecular Dynamics, Python, SBMOpenMM, Structure Based Modeling},

pubstate = {published},

tppubtype = {article}

}

@article{pmid29035170,

title = {Abstracts from the 8th International Conference on cGMP Generators, Effectors and Therapeutic Implications : Bamberg, Germany. 23-25 June, 2017},

doi = {10.1186/s40360-017-0170-5},

issn = {2050-6511},

year  = {2017},

date = {2017-10-10},

urldate = {2017-10-10},

journal = {BMC Pharmacol Toxicol},

volume = {18},

number = {Suppl 1},

pages = {64},

abstract = {Background:



Guanylate cyclases are important drugs targets for several disorders, including cardiovascular, pulmonary and renal diseases. Only heme-dependent stimulators and heme-independent activators of soluble guanylate cyclases (sGCs) have been amply studied, although even in this case their mechanism of action is unclear. We have recently described the potential binding site of heme-dependent stimulators [1]. In this study, we are: first, investigating the mechanism of action of these heme-dependent stimulators of sGCs, and, second, searching for new modulators of membrane guanylate cyclases (mGCs). In both cases, we are using the recently available structural data for this class of enzymes.



Methods:



Basically, the general procedure includes first comparative modelling of the target protein (based on the satisfaction of spatial restraints), docking of a subset of compounds pertaining to the ZINC-database (Zbc-ZINC Biogenic compounds; 180,313 molecules) to several conformations of the potential “druggable” sites in the proteins of interest, and selection of the compounds with the best score for site specificity. Drugs with poor site and protein specificity are discarded. Molecular dynamics is used for the selection of protein conformations submitted to drug docking (after evaluation of the volume of the cavities during the whole simulation) and to analyze the time-dependent structural changes evoked by the best-scoring compounds. Ligand binding affinities are evaluated by the Linear Interaction Energy (LIE) method [2].



Results and conclusions:



Molecular dynamics of the catalytic domain of human sGC (both, in its inactive and active conformations) in the presence or absence of YC-1 are underway to identify its possible mechanism of action. On the other hand, different sites (including catalytic and receptor domains) of the atrial natriuretic peptide receptor 1 have been submitted to structure-based virtual screening (SBVS) in order to find new modulators of mGCs. Preliminary results of this screening are shown on Table 3 and Fig. 4 for the receptor-binding site.},

keywords = {binding, cGMP, Docking, Electrostatics, Molecular Dynamics},

pubstate = {published},

tppubtype = {article}

}

@article{molinos2017proteoliposomal,

title = {Proteoliposomal formulations of an HIV-1 gp41-based miniprotein elicit a lipid-dependent immunodominant response overlapping the 2F5 binding motif},

author = {Luis M Molinos-Albert and Eneritz Bilbao and Luis Agulló and Silvia Marfil and Elisabet García and Maria Luisa Rodr{'i}guez De La Concepción and Nuria Izquierdo-Useros and Cristina Vilaplana and Jon A Nieto-Garai and F-Xabier Contreras and Martin Floor, Pere J. Cardona, Javier Martinez-Picado, Bonaventura Clotet, Jordi Villà-Freixa, Maier Lorizate, Jorge Carrillo & Julià Blanco},

url = {https://www.nature.com/articles/srep40800},

doi = {10.1038/srep40800},

year  = {2017},

date = {2017-01-01},

urldate = {2017-01-01},

journal = {Scientific reports},

volume = {7},

pages = {40800},

publisher = {Nature Publishing Group},

abstract = {The HIV-1 gp41 Membrane Proximal External Region (MPER) is recognized by broadly neutralizing antibodies and represents a promising vaccine target. However, MPER immunogenicity and antibody activity are influenced by membrane lipids. To evaluate lipid modulation of MPER immunogenicity, we generated a 1-Palmitoyl-2-oleoylphosphatidylcholine (POPC)-based proteoliposome collection containing combinations of phosphatidylserine (PS), GM3 ganglioside, cholesterol (CHOL), sphingomyelin (SM) and the TLR4 agonist monophosphoryl lipid A (MPLA). A recombinant gp41-derived miniprotein (gp41-MinTT) exposing the MPER and a tetanus toxoid (TT) peptide that favors MHC-II presentation, was successfully incorporated into lipid mixtures (>85%). Immunization of mice with soluble gp41-MinTT exclusively induced responses against the TT peptide, while POPC proteoliposomes generated potent anti-gp41 IgG responses using lower protein doses. The combined addition of PS and GM3 or CHOL/SM to POPC liposomes greatly increased gp41 immunogenicity, which was further enhanced by the addition of MPLA. Responses generated by all proteoliposomes targeted the N-terminal moiety of MPER overlapping the 2F5 neutralizing epitope. Our data show that lipids impact both, the epitope targeted and the magnitude of the response to membrane-dependent antigens, helping to improve MPER-based lipid carriers. Moreover, the identification of immunodominant epitopes allows for the redesign of immunogens targeting MPER neutralizing determinants.},

keywords = {Computer Simulation, gp41, HIV, Models: Molecular},

pubstate = {published},

tppubtype = {article}

}

@article{pmid27427875,

title = {Antiretroviral therapy suppressed participants with low CD4+ T-cell counts segregate according to opposite immunological phenotypes},

author = {Josué Pérez-Santiago and Dan Ouchi and Victor Urrea and Jorge Carrillo and Cecilia Cabrera and Jordi Villà-Freixa and Jordi Puig and Roger Paredes and Eugènia Negredo and Bonaventura Clotet and Marta Massanella and Julià Blanco},

doi = {10.1097/QAD.0000000000001205},

issn = {1473-5571},

year  = {2016},

date = {2016-09-24},

urldate = {2016-09-24},

journal = {AIDS},

volume = {30},

number = {15},

pages = {2275--2287},

abstract = {BACKGROUND: The failure to increase CD4 T-cell counts in some antiretroviral therapy suppressed participants (immunodiscordance) has been related to perturbed CD4 T-cell homeostasis and impacts clinical evolution.



METHODS: We evaluated different definitions of immunodiscordance based on CD4 T-cell counts (cutoff) or CD4 T-cell increases from nadir value (ΔCD4) using supervised random forest classification of 74 immunological and clinical variables from 196 antiretroviral therapy suppressed individuals. Unsupervised clustering was performed using relevant variables identified in the supervised approach from 191 individuals.



RESULTS: Cutoff definition of CD4 cell count 400 cells/μl performed better than any other definition in segregating immunoconcordant and immunodiscordant individuals (85% accuracy), using markers of activation, nadir and death of CD4 T cells. Unsupervised clustering of relevant variables using this definition revealed large heterogeneity between immunodiscordant individuals and segregated participants into three distinct subgroups with distinct production, programmed cell-death protein-1 (PD-1) expression, activation and death of T cells. Surprisingly, a nonnegligible number of immunodiscordant participants (22%) showed high frequency of recent thymic emigrants and low CD4 T-cell activation and death, very similar to immunoconcordant participants. Notably, human leukocyte antigen - antigen D related (HLA-DR) PD-1 and CD45RA expression in CD4 T cells allowed reproducing subgroup segregation (81.4% accuracy). Despite sharp immunological differences, similar and persistently low CD4 values were maintained in these participants over time.



CONCLUSION: A cutoff value of CD4 T-cell count 400 cells/μl classified better immunodiscordant and immunoconcordant individuals than any ΔCD4 classification. Immunodiscordance may present several, even opposite, immunological patterns that are identified by a simple immunological follow-up. Subgroup classification may help clinicians to delineate diverse approaches that may be needed to boost CD4 T-cell recovery.},

keywords = {CD4+, Data analysis, HIV},

pubstate = {published},

tppubtype = {article}

}

@article{pmid27364190,

title = {Computational exploration of the binding mode of heme-dependent stimulators into the active catalytic domain of soluble guanylate cyclase},

author = {Luis Agulló and Ignasi Buch and Hugo Gutiérrez-de-Terán and David Garcia-Dorado and Jordi Villà-Freixa},

doi = {10.1002/prot.25096},

issn = {1097-0134},

year  = {2016},

date = {2016-07-01},

urldate = {2016-07-01},

journal = {Proteins},

volume = {84},

number = {10},

pages = {1534--1548},

abstract = {Soluble guanylate cyclase (sGC), the main target of nitric oxide (NO), has been proven to have a significant role in coronary artery disease, pulmonary hypertension, erectile dysfunction, and myocardial infarction. One of its agonists, BAY 41-2272 (Riociguat), has been recently approved for treatment of pulmonary arterial hypertension (PHA), while some others are in clinical phases of development. However, the location of the binding sites for the two known types of agonists, heme-dependent stimulators and heme-independent activators, is a matter of debate, particularly for the first group where both a location on the regulatory (H-NOX) and on the catalytic domain have been suggested by different authors. Here, we address its potential location on the catalytic domain, the unique well characterized at the structural level, by an "in silico" approach. Homology models of the catalytic domain of sGC in "inactive" or "active" conformations were constructed using the structure of previously described crystals of the catalytic domains of "inactive" sGCs (2WZ1, 3ET6) and of "active" adenylate cyclase (1CJU). Each model was submitted to six independent molecular dynamics simulations of about 1 μs. Docking of YC-1, a classic heme-dependent stimulator, to all frames of representative trajectories of "inactive" and "active" conformations, followed by calculation of absolute binding free energies with the linear interaction energy (LIE) method, revealed a potential high-affinity binding site on the "active" structure. The site, located between the pseudo-symmetric and the catalytic site just over the loop β2 -β3 , does not overlap with the forskolin binding site on adenylate cyclases. Proteins 2016; 84:1534-1548. © 2016 Wiley Periodicals, Inc.},

keywords = {AMBER, AutoDock, binding, cGMP, chemistry; Enzymes, Docking, Electrostatics, NO, Soluble Guanylate Cyclase},

pubstate = {published},

tppubtype = {article}

}

@article{pmid25221446,

title = {TRIFORCE: Tessellated Semianalytical Solvent Exposed Surface Areas and Derivatives},

author = {Nils J D Drechsel and Christopher J Fennell and Ken A Dill and Jordi Villà-Freixa},

doi = {10.1021/ct5002818},

issn = {1549-9626},

year  = {2014},

date = {2014-09-09},

urldate = {2014-09-09},

journal = {J Chem Theory Comput},

volume = {10},

number = {9},

pages = {4121--4132},

abstract = {We present a new approach to the calculation of solvent-accessible surface areas of molecules with potential application to surface area based methods for determination of solvation free energies. As in traditional analytical and statistical approaches, this new algorithm, called TRIFORCE, reports both component areas and derivatives as a function of the atomic coordinates and radii. Unique to TRIFORCE are the rapid and scalable approaches for the determination of sphere intersection points and numerical estimation of the surface areas, derivatives, and other properties that can be associated with the surface area facets. The algorithm performs a special tessellation and semianalytical integration that uses a precomputed look-up table. This provides a simple way to balance numerical accuracy and memory usage. TRIFORCE calculates derivatives in the same manner, enabling application in force-dependent activities such as molecular geometry minimization. TRIFORCE is available free of charge for academic purposes as both a C++ library, which can be directly interfaced to existing molecular simulation packages, and a web-accessible application.},

keywords = {AMBER, Electrostatics, Non-polar interactions, Solvation},

pubstate = {published},

tppubtype = {article}

}

@article{Tajes2014,

title = {Methylglyoxal Produced by Amyloid $beta$-Peptide-Induced Nitrotyrosination of Triosephosphate Isomerase Triggers Neuronal Death in Alzheimer Disease},

author = {Marta Tajes and Abel Eraso--Pichota and Fanny Rubio--Moscard ó and Biuse Guivernau and Eva Ramos--Fernández and Mònica Bosch--Morató and Francesc Xavier Guix and Jordi Clarimón and Gian Pietro Miscione and Mercé Boada and Toshiharu Suzuki and Henrik Molina and Jordi Villà-Freixa and Rubén Vicente and Francisco J Muñoz},

doi = {10.3233/JAD-131685},

issn = {1875-8908},

year  = {2014},

date = {2014-01-01},

urldate = {2014-01-01},

journal = {J. Alzheimer Dis},

volume = {41},

pages = {273--288},

abstract = {Amyloid-β peptide (Aβ) aggregates induce nitro-oxidative stress, contributing to the characteristic neurodegeneration found in Alzheimer's disease (AD). One of the most strongly nitrotyrosinated proteins in AD is the triosephosphate isomerase (TPI) enzyme which regulates glycolytic flow, and its efficiency decreased when it is nitrotyrosinated. The main aims of this study were to analyze the impact of TPI nitrotyrosination on cell viability and to identify the mechanism behind this effect. In human neuroblastoma cells (SH-SY5Y), we evaluated the effects of Aβ42 oligomers on TPI nitrotyrosination. We found an increased production of methylglyoxal (MG), a toxic byproduct of the inefficient nitro-TPI function. The proapoptotic effects of Aβ42 oligomers, such as decreasing the protective Bcl2 and increasing the proapoptotic caspase-3 and Bax, were prevented with a MG chelator. Moreover, we used a double mutant TPI (Y165F and Y209F) to mimic nitrosative modifications due to Aβ action. Neuroblastoma cells transfected with the double mutant TPI consistently triggered MG production and a decrease in cell viability due to apoptotic mechanisms. Our data show for the first time that MG is playing a key role in the neuronal death induced by Aβ oligomers. This occurs because of TPI nitrotyrosination, which affects both tyrosines associated with the catalytic center.},

keywords = {Alzheimer disease, chemistry; Enzymes, QM/MM, TPI, Triosephosphate isomerase},

pubstate = {published},

tppubtype = {article}

}

@article{Mulero2013,

title = {Chromatin-Bound IkBa Regulates a Subset of Polycomb Target Genes in Differentiation and Cancer},

author = {Maria Dolors Ferres-Marco and Abul Islam and Pol Margalef and Matteo Pecoraro and Agustí and Nils Drechsel and Cristina Charneco and Shelly Davis and Nicola and Fernando Gallardo and Erika López and Elena Asensio-Juan and Verónica and Jessica González and Mar Iglesias and Vincent Shih and Mar Alb and Luciano Di Croce and Alexander Hoffmann and Shigeki Miyamoto and Jordi Villà-Freixa and Nuria López and William M Keyes and Mar{'i}a Domínguez and Anna Bigas and Lluís Espinosa},

url = {http://www.sciencedirect.com/science/article/pii/S1535610813002791},

doi = {http://dx.doi.org/10.1016/j.ccr.2013.06.003},

issn = {1535-6108},

year  = {2013},

date = {2013-01-01},

urldate = {2013-01-01},

journal = {Cancer Cell},

volume = {24},

number = {2},

pages = {151-166},

abstract = {IκB proteins are the primary inhibitors of NF-κB. Here, we demonstrate that sumoylated and phosphorylated IκBα accumulates in the nucleus of keratinocytes and interacts with histones H2A and H4 at the regulatory region of HOX and IRX genes. Chromatin-bound IκBα modulates Polycomb recruitment and imparts their competence to be activated by TNFα. Mutations in the Drosophila IκBα gene cactus enhance the homeotic phenotype of Polycomb mutants, which is not counteracted by mutations in dorsal/NF-κB. Oncogenic transformation of keratinocytes results in cytoplasmic IκBα translocation associated with a massive activation of Hox. Accumulation of cytoplasmic IκBα was found in squamous cell carcinoma (SCC) associated with IKK activation and HOX upregulation},

keywords = {Docking, Electrostatics, Molecular Dynamics, Molecular Modeling},

pubstate = {published},

tppubtype = {article}

}

@article{Dalton2012,

title = {New model of CFTR proposes active channel-like conformation},

author = {James Dalton and Ori Kalid and Maya Schushan and Nir Ben-Tal and Jordi Villà--Freixa},

url = {http://www.ncbi.nlm.nih.gov/pubmed/22747419},

year  = {2012},

date = {2012-01-01},

urldate = {2012-01-01},

journal = {J. Chem. Inf. Model.},

volume = {52(7)},

pages = {1842--1853},

abstract = {The cystic fibrosis transmembrane conductance regulator (CFTR) is an unusual ABC transporter, functioning as a chloride channel critical for fluid homeostasis in multiple organs. Disruption of CFTR function is associated with cystic fibrosis making it an attractive therapeutic target. In addition, CFTR blockers are being developed as potential antidiarrheals. CFTR drug discovery is hampered by the lack of high resolution structural data, and considerable efforts have been invested in modeling the channel structure. Although previously published CFTR models that have been made publicly available mostly agree with experimental data relating to the overall structure, they present the channel in an outward-facing conformation that does not agree with expected properties of a "channel-like" structure. Here, we make available a model of CFTR in such a "channel-like" conformation, derived by a unique modeling approach combining restrained homology modeling and ROSETTA refinement. In contrast to others, the present model is in agreement with expected channel properties such as pore shape, dimensions, solvent accessibility, and experimentally derived distances. We have used the model to explore the interaction of open channel blockers within the pore, revealing a common binding mode and ionic interaction with K95, in agreement with experimental data. The binding-site was further validated using a virtual screening enrichment experiment, suggesting the model might be suitable for drug discovery. In addition, we subjected the model to a molecular dynamics simulation, revealing previously unaddressed salt-bridge interactions that may be important for structure stability and pore-lining residues that may take part in Cl(-) conductance.},

keywords = {CFTR, chemistry/metabolism; Ion Channels, Molecular Dynamics, Molecular Modeling},

pubstate = {published},

tppubtype = {article}

}

@article{Margalef2012,

title = {A novel truncated form of IKK$alpha$ is responsible for nuclear IKK activity in colorectal cancer},

author = {Pol Margalef and Vanessa Fernández-Majada and Alberto Villanueva and Ricard Garcia-Carbonell and Mar Iglesias and Laura López and María Martínez-Iniesta and Jordi Villà-Freixa and Mari Carmen Mulero and Montserrat Andreu and Ferran Torres and Marty W Mayo and Anna Bigas and Lluís Espinosa},

url = {http://www.cell.com/cell-reports/abstract/S2211-1247(12)00268-9},

doi = {10.1016/j.celrep.2012.08.028},

year  = {2012},

date = {2012-01-01},

urldate = {2012-01-01},

journal = {Cell Rep.},

volume = {2},

pages = {840-854},

abstract = {Nuclear IKKα regulates gene transcription by phosphorylating specific substrates and has been linked to cancer progression and metastasis. However, the mechanistic connection between tumorigenesis and IKKα activity remains poorly understood. We have now analyzed 288 human colorectal cancer samples and found a significant association between the presence of nuclear IKK and malignancy. Importantly, the nucleus of tumor cells contains an active IKKα isoform with a predicted molecular weight of 45 kDa (p45-IKKα) that includes the kinase domain but lacks several regulatory regions. Active nuclear p45-IKKα forms a complex with nonactive IKKα and NEMO that mediates phosphorylation of SMRT and histone H3. Proteolytic cleavage of FL-IKKα into p45-IKKα is required for preventing the apoptosis of CRC cells in vitro and sustaining tumor growth in vivo. Our findings identify a potentially druggable target for treating patients with advance refractory CRC.},

keywords = {chemistry; Enzymes, NF-KB, Proteases, Python},

pubstate = {published},

tppubtype = {article}

}

@article{VillaFreixa2011,

title = {Simulacions moleculars de la recativitat enzim`atica: dissecant contribucions amb l'ajut d'un ordinador},

author = {Jordi Villà-Freixa},

url = {http://publicacions.iec.cat/PopulaFitxa.do?moduleName=revistes_cientifiques&subModuleName=&idColleccio=215},

year  = {2011},

date = {2011-01-01},

urldate = {2011-01-01},

journal = {Omnis Cellula},

volume = {26},

pages = {8},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{Jana2011,

title = {A QM/MM Study of the Last Two Steps of the Catalytic Cycle of Acetohydroxyacid Synthase},

author = {Gonzalo Jaña and Verónica Jiménez and Jordi Villà-Freixa and Xavier Prat-Resina and Eduardo Delgado and Joel Alderete},

url = {http://dx.doi.org/10.1016/j.comptc.2011.02.030},

year  = {2011},

date = {2011-01-01},

urldate = {2011-01-01},

journal = {Computational and Theoretical Chemistry},

volume = {966},

pages = {159--166},

abstract = {The acetohydroxyacid synthase (AHAS) is a thiamin diphosphate dependent enzyme that participates in the biosynthetic pathway of branched-chain amino acids. The catalytic cycle of AHAS consists of five steps and the first three steps are analogues to other thiamin diphosphate dependent enzymes, but some mechanism aspect of the last two steps of the AHAS catalytic cycle remain unclear. We have modeled the last two catalytic steps of the AHAS, using a combined quantum mechanical and molecular mechanical method (QM/MM). Substrates (pyruvate and hydroxyethylthiamine diphosphate anion) and three important amino acids (Arg380, Gly116 and Glu139) of the active site were considered into the QM region. A complete characterization of the potential energy surface was performed using the AM1/CHARMM27 approach. In order to improve the semi-empirical calculations, the AM1/MM potential energy surface was corrected at B3LYP/6-31G(d,p) level (B3LYP/6-31G(d,p)//AM1/MM). Our results show that the protein environment is crucial to provide an adequate description of the reaction mechanisms. This fact is consequence of the increase of the substrate polarization by the enzyme environment. In this sense, the largest substrate polarization is observed when selected amino acid residues are included within the QM region in B3LYP/6-31G(d,p)//AM1/MM calculations.},

keywords = {Acetohydroxyacid Synthase, chemistry; Enzymes, QM/MM},

pubstate = {published},

tppubtype = {article}

}

@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 = {Adun, Computer code, Free energy calculations, Multiscale simulations, Objective C},

pubstate = {published},

tppubtype = {article}

}

@article{Lawford2011,

title = {Virtual physiological human: training challenges},

author = {Patricia V Lawford and Andrew V Narracott and Keith McCormack and Jesus Bisbal and Carlos Martin and Bart Bijnens and Bindi Brook and Margarita Zachariou and Jordi Villà-Freixa and Peter Kohl and Katherine Fletcher and Vanessa Diaz-Zuccarini},

url = {http://rsta.royalsocietypublishing.org/content/369/1935/494.long},

doi = {10.1098/rsta.2010.0307},

year  = {2011},

date = {2011-01-01},

urldate = {2011-01-01},

journal = {Philosophical Transactions of the Royal Society A: Mathematical,Physical and Engineering Sciences},

volume = {369},

number = {1935},

pages = {494},

keywords = {Systems Biology},

pubstate = {published},

tppubtype = {article}

}

@article{Maier2010,

title = {Knowledge Management for Systems Biology; a general and visually driven framework applied to translational medicine},

author = {Dieter Maier and Wenzel Kalus and Martin Wolff and Susana G Kalko and Josep Roca and Igor Mar 'i and Nil Turan and Marta Cascante and Francesco Falciani and Miguel Hernández and Jordi Villà-Freixa and Sascha Losko},

url = {http://www.biomedcentral.com/1752-0509/5/38},

year  = {2011},

date = {2011-01-01},

urldate = {2011-01-01},

journal = {BMC Syst. Biol.},

volume = {5},

pages = {38},

abstract = {Background

To enhance our understanding of complex biological systems like diseases we need to put all of the available data into context and use this to detect relations, pattern and rules which allow predictive hypotheses to be defined. Life science has become a data rich science with information about the behaviour of millions of entities like genes, chemical compounds, diseases, cell types and organs, which are organised in many different databases and/or spread throughout the literature. Existing knowledge such as genotype - phenotype relations or signal transduction pathways must be semantically integrated and dynamically organised into structured networks that are connected with clinical and experimental data. Different approaches to this challenge exist but so far none has proven entirely satisfactory.



Results

To address this challenge we previously developed a generic knowledge management framework, BioXM™, which allows the dynamic, graphic generation of domain specific knowledge representation models based on specific objects and their relations supporting annotations and ontologies. Here we demonstrate the utility of BioXM for knowledge management in systems biology as part of the EU FP6 BioBridge project on translational approaches to chronic diseases. From clinical and experimental data, text-mining results and public databases we generate a chronic obstructive pulmonary disease (COPD) knowledge base and demonstrate its use by mining specific molecular networks together with integrated clinical and experimental data.



Conclusions

We generate the first semantically integrated COPD specific public knowledge base and find that for the integration of clinical and experimental data with pre-existing knowledge the configuration based set-up enabled by BioXM reduced implementation time and effort for the knowledge base compared to similar systems implemented as classical software development projects. The knowledgebase enables the retrieval of sub-networks including protein-protein interaction, pathway, gene - disease and gene - compound data which are used for subsequent data analysis, modelling and simulation. Pre-structured queries and reports enhance usability; establishing their use in everyday clinical settings requires further simplification with a browser based interface which is currently under development.},

keywords = {Systems Biology},

pubstate = {published},

tppubtype = {article}

}

@article{Jana2010,

title = {Computational study on the carboligation reaction of acetohidroxyacid synthase: new approach on the role of the HEThDP- intermediate.},

author = {Gonzalo Jaña and Verónica Jiménez and Jordi Villà-Freixa and Xavier Prat-Resina and Eduardo Delgado and Joel Alderete},

url = {http://dx.doi.org/10.1002/prot.22693},

doi = {10.1002/prot.22693},

year  = {2010},

date = {2010-05-01},

urldate = {2010-05-01},

journal = {Proteins},

volume = {78},

number = {7},

pages = {1774--1788},

institution = {Grupo de Qu'imica Teórica y Computacional, Facultad de Ciencias Qu'imicas, Universidad de Concepción, Casilla 160-C, Concepción, Chile.},

abstract = {Acetohydroxyacid synthase (AHAS) is a thiamin diphosphate dependent 

	enzyme that catalyses the decarboxylation of pyruvate to yield the 

	hydroxyethyl-thiamin diphosphate (ThDP) anion/enamine intermediate 

	(HEThDP(-)). This intermediate reacts with a second ketoacid to form 

	acetolactate or acetohydroxybutyrate as products. Whereas the mechanism 

	involved in the formation of HEThDP(-) from pyruvate is well understood, 

	the role of the enzyme in controlling the carboligation reaction 

	of HEThDP(-) has not been determined yet. In this work, molecular 

	dynamics (MD) simulations were employed to identify the aminoacids 

	involved in the carboligation stage. These MD studies were carried 

	out over the catalytic subunit of yeast AHAS containing the reaction 

	intermediate (HEThDP(-)) and a second pyruvate molecule. Our results 

	suggest that additional acid-base ionizable groups are not required 

	to promote the catalytic cycle, in contrast with earlier proposals. 

	This finding leads us to postulate that the formation of acetolactate 

	relies on the acid-base properties of the HEThDP(-) intermediate 

	itself. PM3 semiempirical calculations were employed to obtain the 

	energy profile of the proposed mechanism on a reduced model of the 

	active site. These calculations confirm the role of HEThDP(-) intermediate 

	as the ionizable group that promotes the carboligation and product 

	formation steps of the catalytic cycle.},

keywords = {chemistry; Enzymes, QM/MM},

pubstate = {published},

tppubtype = {article}

}

@article{Cooper2010,

title = {The Virtual Physiological Human Toolkit},

author = {Johnathan Cooper and Frederic Cervenansky and Gianni de Fabritiis and John Fenner and Denis Friboulet and Toni Giorgino and Steven Manos and Yves Martelli and Jordi Villà-Freixa and Stefan Zasada and Sharon Lloyd and Keith McCormack and Peter V Coveney},

url = {http://www.ncbi.nlm.nih.gov/pubmed/20643685},

year  = {2010},

date = {2010-01-01},

urldate = {2010-01-01},

journal = {Phil. Trans. R. Soc. A},

volume = {368},

pages = {3925--3936},

keywords = {Multiscale simulations, Systems Biology, VPH},

pubstate = {published},

tppubtype = {article}

}

@article{Garcia2010,

title = {Statistical Analysis of Global Connectivity and Activity Distributions in Cellular Networks},

author = {Adrián L García--Lomana and Qasim Beg and Gianni de Fabritiis and Jordi Villà-Freixa},

url = {http://arxiv.org/abs/1004.3138},

year  = {2010},

date = {2010-01-01},

urldate = {2010-01-01},

journal = {J. Comput. Biol.},

volume = {17(7)},

pages = {869--878},

abstract = {Various molecular interaction networks have been claimed to follow 

	power-law decay for their global connectivity distribution. It has 

	been proposed that there may be underlying generative models that 

	explain this heavy-tailed behavior by self-reinforcement processes 

	such as classical or hierarchical scale-free network models. Here 

	we analyze a comprehensive data set of protein-protein and transcriptional 

	regulatory interaction networks in yeast, an textitE. coli metabolic 

	network, and gene activity profiles for different metabolic states 

	in both organisms. We show that in all cases the networks have a 

	heavy-tailed distribution, but most of them present significant differences 

	from a power-law model according to a stringent statistical test. 

	Those few data sets that have a statistically significant fit with 

	a power-law model follow other distributions equally well. Thus, 

	while our analysis supports that both global connectivity interaction 

	networks and activity distributions are heavy-tailed, they are not 

	generally described by any specific distribution model, leaving space 

	for further inferences on generative models.},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{Rue2010,

title = {Simulation Methods with Extended Stability for Stiff Biochemical Kinetics},

author = {Pau Rué and Jordi Villà-Freixa and Kevin Burrage},

url = {http://www.biomedcentral.com/1752-0509/4/110},

doi = {10.1186/1752-0509-4-110},

year  = {2010},

date = {2010-01-01},

urldate = {2010-01-01},

journal = {BMC Syst. Biol.},

volume = {4},

pages = {110},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{Guix2009,

title = {Amyloid-dependent triosephosphate isomerase nitrotyrosination induces glycation and tau fibrillation},

author = {Francesc X Guix and Gerard Ill-Raga and Ramona Bravo and Tadashi Nakaya and Gianni de Fabritiis and Mireia Coma and Gian Pietro Miscione and Jordi Villà-Freixa and Toshiharu Suzuki and Xavier Fernandez-Busquets and Miguel A Valverde and Bart de Strooper and Francisco J Munoz},

url = {http://brain.oxfordjournals.org/cgi/content/abstract/132/5/1335},

doi = {10.1093/brain/awp023},

year  = {2009},

date = {2009-01-01},

urldate = {2009-01-01},

journal = {Brain},

volume = {132},

number = {5},

pages = {1335-1345},

abstract = {Alzheimer's disease neuropathology is characterized by neuronal death, 

	amyloid beta-peptide deposits and neurofibrillary tangles composed 

	of paired helical filaments of tau protein. Although crucial for 

	our understanding of the pathogenesis of Alzheimer's disease, the 

	molecular mechanisms linking amyloid beta-peptide and paired helical 

	filaments remain unknown. Here, we show that amyloid beta-peptide-induced 

	nitro-oxidative damage promotes the nitrotyrosination of the glycolytic 

	enzyme triosephosphate isomerase in human neuroblastoma cells. Consequently, 

	nitro-triosephosphate isomerase was found to be present in brain 

	slides from double transgenic mice overexpressing human amyloid precursor 

	protein and presenilin 1, and in Alzheimer's disease patients. Higher 

	levels of nitro-triosephosphate isomerase (P < 0.05) were detected, 

	by Western blot, in immunoprecipitates from hippocampus (9 individuals) 

	and frontal cortex (13 individuals) of Alzheimer's disease patients, 

	compared with healthy subjects (4 and 9 individuals, respectively). 

	Triosephosphate isomerase nitrotyrosination decreases the glycolytic 

	flow. Moreover, during its isomerase activity, it triggers the production of the highly neurotoxic methylglyoxal (n = 4; P < 0.05). The bioinformatics 

	simulation of the nitration of tyrosines 164 and 208, close to the 

	catalytic centre, fits with a reduced isomerase activity. Human embryonic 

	kidney (HEK) cells overexpressing double mutant triosephosphate isomerase 

	(Tyr164 and 208 by Phe164 and 208) showed high methylglyoxal production. 

	This finding correlates with the widespread glycation immunostaining 

	in Alzheimer's disease cortex and hippocampus from double transgenic 

	mice overexpressing amyloid precursor protein and presenilin 1. Furthermore, 

	nitro-triosephosphate isomerase formed large beta-sheet aggregates 

	in vitro and in vivo, as demonstrated by turbidometric analysis and 

	electron microscopy. Transmission electron microscopy (TEM) and atomic 

	force microscopy studies have demonstrated that nitro-triosephosphate 

	isomerase binds tau monomers and induces tau aggregation to form 

	paired helical filaments, the characteristic intracellular hallmark 

	of Alzheimer's disease brains. Our results link oxidative stress, 

	the main etiopathogenic mechanism in sporadic Alzheimer's disease, 

	via the production of peroxynitrite and nitrotyrosination of triosephosphate 

	isomerase, to amyloid beta-peptide-induced toxicity and tau pathology.},

keywords = {Alzheimer disease, chemistry; Enzymes, Molecular Modeling, QM/MM, TIM},

pubstate = {published},

tppubtype = {article}

}

@article{Scheper2009,

title = {Analysis of electrostatic contributions to the selectivity of interactions between RING-finger domains and ubiquitin-conjugating enzymes.},

author = {Johanna Scheper and Baldo Oliva and Jordi Villà-Freixa and Timothy M Thomson},

url = {http://dx.doi.org/10.1002/prot.22120},

doi = {10.1002/prot.22120},

year  = {2009},

date = {2009-01-01},

urldate = {2009-01-01},

journal = {Proteins},

volume = {74},

number = {1},

pages = {92--103},

institution = {Department of Molecular and Cell Biology, Instituto de Biolog’a Molecular de Barcelona, Consejo Superior de Investigaciones Cient’ficas, Barcelona, Spain.},

abstract = {The zinc-coordinated protein motifs known as RING-finger domains, 

	present on a class of ubiquitin ligases (E3's), recruit ubiquitin-conjugating 

	enzymes (E2s), tethering them to substrate proteins for covalent 

	modification with ubiquitin. Each RING-finger domain can recruit 

	different E2s, and these interactions are frequently selective, in 

	that certain RING-finger domains associate preferentially with certain 

	E2s. This selectivity acquires particular biological relevance when 

	the recruited E2s exert specialized functions. We have explored the 

	determinants that specify the presence or absence of experimentally 

	detectable interaction between two RING-finger domains, those on 

	RNF11 and RNF103, and two E2s, UBC13, a specialized E2 that catalyzes 

	ubiquitin chain elongation through Lys63 of ubiquitin, and UbcH7, 

	which mediates polyubiquitylation through Lys48. Through the iterative 

	use of computational predictive tools and experimental validations, 

	we have found that these interactions and their selectivity are partly 

	governed by the combinations of electrostatic interactions linking 

	specific residues of the contact interfaces. Our analysis also predicts 

	that the main determinants of selectivity of these interactions reside 

	on the RING-finger domains, rather than on the E2s. The application 

	of some of these rules of interaction selectivity has permitted us 

	to experimentally manipulate the selectivity of interaction of the 

	RING-finger domain-E2 pairs under study.},

keywords = {Binding Sites; Carrier Proteins, Chemical; Nerve Tissue Proteins, chemistry/metabolism; Humans; Models, chemistry/metabolism; Point Mutation; Protein Binding; RING Finger Domains; Simulation; Static Electricity; Ubiquitin-Conjugating Enzymes, metabolism, metabolism; Ubiquitin-Protein Ligases},

pubstate = {published},

tppubtype = {article}

}

@article{Fabritiis2008,

title = {Energetics of K+ permeability through Gramicidin A by forward-reverse steered molecular dynamics.},

author = {De G Fabritiis and P V Coveney and J Villà-Freixa},

url = {http://dx.doi.org/10.1002/prot.22036},

doi = {10.1002/prot.22036},

year  = {2008},

date = {2008-10-01},

urldate = {2008-10-01},

journal = {Proteins},

volume = {73},

number = {1},

pages = {185--194},

institution = {Computational Biochemistry and Biophysics Laboratory (GRIB-IMIM), Universitat Pompeu Fabra, Barcelona Biomedical Research Park, C/Dr Aiguader 88, 08003 Barcelona, Spain. gianni.defabritiis@upf.edu},

abstract = {The estimation of ion channel permeability poses a considerable challenge 

	for computer simulations because of the significant free energy barriers 

	involved, but also offers valuable molecular information on the ion 

	permeation process not directly available from experiments. In this 

	article we determine the equilibrium free energy barrier for potassium 

	ion permeability in Gramicidin A in an efficient way by atomistic 

	forward-reverse non-equilibrium steered molecular dynamics simulations, 

	opening the way for its use in more complex biochemical systems. 

	Our results indicate that the tent-shaped energetics of translocation 

	of K+ ions in Gramicidin A is dictated by the different polarization 

	responses to the ion of the external bulk water and the less polar 

	environment of the membrane.},

keywords = {chemistry; Thermodynamics, chemistry/metabolism; Ion Channels, chemistry/metabolism; Ion Transport; Models, Computer Simulation; Gramicidin, Molecular; Permeability; Potassium},

pubstate = {published},

tppubtype = {article}

}

@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 = {ByoDyn, Development, gene regulatory networks, Mathematical modeling, Optimal design, Optimization, Systems Biology},

pubstate = {published},

tppubtype = {article}

}