National Institute of Bioinformatics

Valencia, Spain

National Institute of Bioinformatics

Valencia, Spain
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Drsata T.,Czech Institute of Organic Chemistry And Biochemistry | Drsata T.,Academy of Sciences of the Czech Republic | Perez A.,State University of New York at Stony Brook | Orozco M.,Barcelona Supercomputing Center | And 6 more authors.
Journal of Chemical Theory and Computation | Year: 2013

The Dickerson-Drew dodecamer (DD) d[CGCGAATTCGCG]2 is a prototypic B-DNA molecule whose sequence-specific structure and dynamics have been investigated by many experimental and computational studies. Here, we present an analysis of DD properties based on extensive atomistic molecular dynamics (MD) simulations using different ionic conditions and water models. The 0.6-2.4-μs-long MD trajectories are compared to modern crystallographic and NMR data. In the simulations, the duplex ends can adopt an alternative base-pairing, which influences the oligomer structure. A clear relationship between the BI/BII backbone substates and the basepair step conformation has been identified, extending previous findings and exposing an interesting structural polymorphism in the helix. For a given end pairing, distributions of the basepair step coordinates can be decomposed into Gaussian-like components associated with the BI/BII backbone states. The nonlocal stiffness matrices for a rigid-base mechanical model of DD are reported for the first time, suggesting salient stiffness features of the central A-tract. The Riemann distance and Kullback-Leibler divergence are used for stiffness matrix comparison. The basic structural parameters converge very well within 300 ns, convergence of the BI/BII populations and stiffness matrices is less sharp. Our work presents new findings about the DD structural dynamics, mechanical properties, and the coupling between basepair and backbone configurations, including their statistical reliability. The results may also be useful for optimizing future force fields for DNA. © 2012 American Chemical Society.

Gonzalez S.,Joint IRB BSC program on Computational Biology | Montserrat-sentis B.,Joint IRB BSC program on Computational Biology | Sanchez F.,Polytechnic University of Catalonia | Puiggros M.,Joint IRB BSC program on Computational Biology | And 5 more authors.
Bioinformatics | Year: 2012

Motivation: The prediction and annotation of the genomic regions involved in gene expression has been largely explored. Most of the energy has been devoted to the development of approaches that detect transcription start sites, leaving the identification of regulatory regions and their functional transcription factor binding sites (TFBSs) largely unexplored and with important quantitative and qualitative methodological gaps. Results: We have developed ReLA (for REgulatory region Local Alignment tool), a unique tool optimized with the Smith-Waterman algorithm that allows local searches of conserved TFBS clusters and the detection of regulatory regions proximal to genes and enhancer regions. ReLA's performance shows specificities of 81 and 50% when tested on experimentally validated proximal regulatory regions and enhancers, respectively. © The Author(s) 2012. Published by Oxford University Press.

Marabini R.,Autonomous University of Madrid | MacIas J.R.,CSIC - National Center for Biotechnology | Vargas J.,CSIC - National Center for Biotechnology | Quintana A.,CSIC - National Center for Biotechnology | And 4 more authors.
Acta Crystallographica Section D: Biological Crystallography | Year: 2013

Electron microscopy is a valuable tool for elucidating the three-dimensional structures of macromolecular complexes. As the field matures and the number of solved structures increases, the existence of infrastructures that keep this information organized and accessible is crucial. At the same time, standards and clearly described conventions facilitate software maintenance, benefit interoperability with other packages and allow data interchange. This work describes three developments promoting integrative biology, standardization and workflow processing, namely PeppeR, the EMX initiative and Scipion. © 2013 International Union of Crystallography Printed in Singapore - all rights reserved.

Faustino I.,Barcelona Institute for Research in Biomedicine | Faustino I.,Barcelona Supercomputing Center | Perez A.,Barcelona Institute for Research in Biomedicine | Perez A.,Barcelona Supercomputing Center | And 3 more authors.
Biophysical Journal | Year: 2010

The structure and flexibility of the RNA duplex has been studied using extended molecular dynamics simulations on four diverse 18-mer oligonucleotides designed to contain many copies of the 10 unique dinucleotide steps in different sequence environments. Simulations were performed using the two most popular force fields for nucleic acids simulations (AMBER and CHARMM) in their latest versions, trying to arrive to a consensus picture of the RNA flexibility. Contrary to what was found for DNA duplex ( DNA 2), no clear convergence is found for the RNA duplex (RNA2), but one of the force field seems to agree better with experimental data. MD simulations performed with this force field were used to fully characterize, for the first time to our knowledge, the sequence-dependent elastic properties of RNA duplexes at different levels of resolutions. The flexibility pattern of RNA2 shows similarities with DNA 2, but also surprising differences, which help us to understand the different biological functions of both molecules. A full mesoscopic model of RNA duplex at different resolution levels is derived to be used for genome-wide description of the flexibility of double-helical fragments of RNA. © 2010 by the Biophysical Society.

Raimondi F.,Dulbecco Telethon Institute | Orozco M.,Barcelona Institute for Research in Biomedicine | Orozco M.,Barcelona Supercomputing Center | Orozco M.,National Institute of Bioinformatics | Fanelli F.,Dulbecco Telethon Institute
Structure | Year: 2010

The evolutionary and physical deformability patterns of members of the Ras GTPase superfamily were investigated by Principal Component and Elastic Network-Normal Mode analyses. The study helped to decipher the dynamics information encrypted into the conserved core and to separate the trans-family intrinsic flexibility associated with a common function from the protein motions related to functional specialization of selected families or family members. The conserved core is dynamically divided into two lobes. The deformation modes, which allow the Ras GTPases to accomplish their switching function, are conserved along evolution and are localized in lobe 1 portions close to the nucleotide. These modes lead to functional specialization when associated with evolution-driven deformations of protein portions essentially located in lobe 2, distal from the nucleotide, and involved in peculiar interactions with membrane, guanine nucleotide exchange factors, or effectors. Overall, a complete picture of the functional and evolutionary dynamics of the Ras superfamily emerges. © 2010 Elsevier Ltd. All rights reserved.

Emperador A.,Barcelona Institute for Research in Biomedicine | Emperador A.,Barcelona Supercomputing Center | Meyer T.,Barcelona Institute for Research in Biomedicine | Meyer T.,Barcelona Supercomputing Center | And 4 more authors.
Proteins: Structure, Function and Bioinformatics | Year: 2010

We have applied all atoms discrete molecular dynamics (DMD) based on a quasiphysical potential to study the flexibility of an extended set of proteins for which atomistic MD simulations are available. The method uses pure physical potentials supplemented by information on secondary structure and despite its simplicity is able to reproduce with good accuracy the dynamics of proteins in solution. The method presents a clear improvement with respect to coarse-grained methods based on structure potentials and opens the possibility to explore dynamics of proteins out from the equilibrium and to trace conformational changes induced by interaction of proteins with both small and macromolecular ligands. © 2009 Wiley-Liss, Inc.

Pons C.,Barcelona Supercomputing Center | Pons C.,National Institute of Bioinformatics | Talavera D.,University of Manchester | De La Cruz X.,CSIC IBMB | And 5 more authors.
Journal of Chemical Information and Modeling | Year: 2011

A detailed and complete structural knowledge of the interactome is one of the grand challenges in Biology, and a variety of computational docking approaches have been developed to complement experimental efforts and help in the characterization of protein-protein interactions. Among the different docking scoring methods, those based on physicochemical considerations can give the maximum accuracy at the atomic level, but they are usually computationally demanding and necessarily noisy when implemented in rigid-body approaches. Coarser-grained knowledge-based potentials are less sensitive to details of atomic arrangements, thus providing an efficient alternative for scoring of rigid-body docking poses. In this study, we have extracted new statistical potentials from intermolecular pairs of exposed residues in known complex structures, which were then used to score protein-protein docking poses. The new method, called SIPPER (scoring by intermolecular pairwise propensities of exposed residues), combines the value of residue desolvation based on solvent-exposed area with the propensity-based contribution of intermolecular residue pairs. This new scoring function found a near-native orientation within the top 10 predictions in nearly one-third of the cases of a standard docking benchmark and proved to be also useful as a filtering step, drastically reducing the number of docking candidates needed by energy-based methods like pyDock. © 2011 American Chemical Society.

Portella G.,Barcelona Institute for Research in Biomedicine | Portella G.,Barcelona Supercomputing Center | Orozco M.,Barcelona Institute for Research in Biomedicine | Orozco M.,Barcelona Supercomputing Center | And 2 more authors.
Angewandte Chemie - International Edition | Year: 2010

DNA perming: Folding of a small DNA hairpin from an extended conformation follows two main folding pathways: direct folding (green arrows) and detrapping from non-native compact structures (red arrows). (Also shown: guanosine 5 G anti form.) © 2010 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim.

Raimondi F.,University of Modena and Reggio Emilia | Portella G.,Barcelona Supercomputing Center | Orozco M.,Barcelona Supercomputing Center | Orozco M.,National Institute of Bioinformatics | Fanelli F.,University of Modena and Reggio Emilia
PLoS Computational Biology | Year: 2011

The Ras superfamily comprises many guanine nucleotide-binding proteins (G proteins) that are essential to intracellular signal transduction. The guanine nucleotide-dependent intrinsic flexibility patterns of five G proteins were investigated in atomic detail through Molecular Dynamics simulations of the GDP- and GTP-bound states (SGDP and SGTP, respectively). For all the considered systems, the intrinsic flexibility of SGDP was higher than that of SGTP, suggesting that Guanine Exchange Factor (GEF) recognition and nucleotide switch require higher amplitude motions than effector recognition or GTP hydrolysis. Functional mode, dynamic domain, and interaction energy correlation analyses highlighted significant differences in the dynamics of small G proteins and Gα proteins, especially in the inactive state. Indeed, SGDP of Gαt, is characterized by a more extensive energy coupling between nucleotide binding site and distal regions involved in GEF recognition compared to small G proteins, which attenuates in the active state. Moreover, mechanically distinct domains implicated in nucleotide switch could be detected in the presence of GDP but not in the presence of GTP. Finally, in small G proteins, functional modes are more detectable in the inactive state than in the active one and involve changes in solvent exposure of two highly conserved amino acids in switches I and II involved in GEF recognition. The average solvent exposure of these amino acids correlates in turn with the rate of GDP release, suggesting for them either direct or indirect roles in the process of nucleotide switch. Collectively, nucleotide binding changes the information flow through the conserved Ras-like domain, where GDP enhances the flexibility of mechanically distinct portions involved in nucleotide switch, and favors long distance allosteric communication (in Gα proteins), compared to GTP. © 2011 Raimondi et al.

Carrillo O.,Barcelona Supercomputing Center | Laughton C.A.,University of Nottingham | Orozco M.,Barcelona Supercomputing Center | Orozco M.,National Institute of Bioinformatics | Orozco M.,University of Barcelona
Journal of Chemical Theory and Computation | Year: 2012

We present a new method for fast molecular dynamics simulations in cases where the new trajectories can be considered a perturbation or a combination of previously stored ones. The method is designed for the postgenomic scenario, where databases such as MoDEL will store curated equilibrium trajectories of all biomolecules (proteins, nucleic acids, etc.) of human interest. We demonstrate that the approach outlined here can, with accuracy and great computational efficiency, reproduce and extend original trajectories, describe dynamical effects due to perturbations (e.g., protein-ligand and protein-protein interactions and protein mutations) and predict the dynamics of large polymeric systems built up from previously studied fragments. The method can work simultaneously with low- and high-resolution pictures of the macromolecule, allowing the level of detail to be matched to that required for obtaining the information of biological interest. © 2012 American Chemical Society.

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