Protein conformational changes are at the heart of cell functions, from signalling to ion transpo... more Protein conformational changes are at the heart of cell functions, from signalling to ion transport. However, the transient nature of the intermediates along transition pathways hampers their experimental detection, making the underlying mechanisms elusive. Here we retrieve dynamic information on the actual transition routes from principal component analysis (PCA) of structurally-rich ensembles and, in combination with coarse-grained simulations, explore the conformational landscapes of five well-studied proteins. Modelling them as elastic networks in a hybrid elastic-network Brownian dynamics simulation (eBDIMS), we generate trajectories connecting stable end-states that spontaneously sample the crystallographic motions, predicting the structures of known intermediates along the paths. We also show that the explored non-linear routes can delimit the lowest energy passages between end-states sampled by atomistic molecular dynamics. The integrative methodology presented here provides...
The stability between helical conformations of homopeptides of alanine, glycine, and aminoisobuty... more The stability between helical conformations of homopeptides of alanine, glycine, and aminoisobutyric acid has been studied by means of quantum-mechanical methods. The influence of peptide length on the relative stability between helical conformations has also been analyzed by means of systematic studies for peptides of size up to 11 residues. Finally, the influence of the solvent has been examined by using self-consistent reaction field methods. The results provide a detailed picture of the modulation exerted by these factors on the helical preferences of these peptides.
Page 1. J. Mol. Model. 1996, 2, 1 -15 * To whom correspondence should be addressed Theoretical Me... more Page 1. J. Mol. Model. 1996, 2, 1 -15 * To whom correspondence should be addressed Theoretical Methods for the Representation of Solvent Modesto Orozco*, Cristobal Alhambra and Xavier Barril Departament de Bioquímica. Facultat de Química. Universitat de Barcelona. ...
Nucleosomes provide additional regulatory mechanisms to transcription and DNA replication by medi... more Nucleosomes provide additional regulatory mechanisms to transcription and DNA replication by mediating the access of proteins to DNA. During the cell cycle chromatin undergoes several conformational changes, however the functional significance of these changes to cellular processes are largely unexplored. Here, we present the first comprehensive genome-wide study of nucleosome plasticity at single base-pair resolution along the cell cycle in Saccharomyces cerevisiae. We determined nucleosome organization with a specific focus on two regulatory regions: transcription start sites (TSSs) and replication origins (ORIs). During the cell cycle, nucleosomes around TSSs display rearrangements in a cyclic manner. In contrast to gap (G1 and G2) phases, nucleosomes have a fuzzier organization during S and M phases, Moreover, the choreography of nucleosome rearrangements correlate with changes in gene expression during the cell cycle, indicating a strong association between nucleosomes and cell...
The Conserved Domain Database (CDD) is a compilation of multiple sequence alignments representing... more The Conserved Domain Database (CDD) is a compilation of multiple sequence alignments representing protein domains conserved in molecular evolution. It has been populated with alignment data from the public collections Pfam and SMART, as well as with contributions ...
ABSTRACTWe present a physics-based machine learning approach to predict in vitro transcription fa... more ABSTRACTWe present a physics-based machine learning approach to predict in vitro transcription factor binding affinities from structural and mechanical DNA properties directly derived from atomistic molecular dynamics simulations. The method is able to predict affinities obtained with techniques as different as uPBM, gcPBM and HT-SELEX with an excellent performance, much better than existing algorithms. Due to its nature, the method can be extended to epigenetic variants, mismatches, mutations, or any non-coding nucleobases. When complemented with chromatin structure information, our in vitro trained method provides also good estimates of in vivo binding sites in yeast.
Motivation The BioExcel Building Blocks (BioBB) library offers a broad collection of wrappers on ... more Motivation The BioExcel Building Blocks (BioBB) library offers a broad collection of wrappers on top of common biomolecular simulation and bioinformatics tools. The possibility to access the library remotely and programmatically increases its usability, allowing individual and sporadic executions and enabling remote workflows. Results BioBB REST API extends and complements the BioBB library offering programmatic access to the collection of biomolecular simulation tools included in the BioExcel Building Blocks library. Molecular Dynamics setup, docking, structure modeling, free energy simulations and flexibility analyses are examples of functionalities included in the endpoints collection. All functionalities are accessible through standard REST API calls, voiding the need for tool installation. Availability and implementation All the information related to the BioBB REST API endpoints is accessible from https://mmb.irbbarcelona.org/biobb-api/. Links to extended documentation, includ...
We have used a variety of theoretical and experimental techniques to study the role of four basic... more We have used a variety of theoretical and experimental techniques to study the role of four basic amino acids–Arginine, Lysine, Ornithine and L-2,4-Diaminobutyric acid–on the structure, flexibility and sequence-dependent stability of DNA. We found that the presence of organic ions stabilizes the duplexes and significantly reduces the difference in stability between AT- and GC-rich duplexes with respect to the control conditions. This suggests that these amino acids, ingredients of the primordial soup during abiogenesis, could have helped to equalize the stability of AT- and GC-rich DNA oligomers, facilitating a general non-catalysed self-replication of DNA. Experiments and simulations demonstrate that organic ions have an effect that goes beyond the general electrostatic screening, involving specific interactions along the grooves of the double helix. We conclude that organic ions, largely ignored in the DNA world, should be reconsidered as crucial structural elements far from mimic...
We present a new coarse grained method for the simulation of duplex DNA. The algorithm uses a gen... more We present a new coarse grained method for the simulation of duplex DNA. The algorithm uses a generalized multi-harmonic model that can represent any multi-normal distribution of helical parameters, thus avoiding caveats of current mesoscopic models for DNA simulation and representing a breakthrough in the field. The method has been parameterized from accurate parmbsc1 atomistic molecular dynamics simulations of all unique tetranucleotide sequences of DNA embedded in long duplexes and takes advantage of the correlation between helical states and backbone configurations to derive atomistic representations of DNA. The algorithm, which is implemented in a simple web interface and in a standalone package reproduces with high computational efficiency the structural landscape of long segments of DNA untreatable by atomistic molecular dynamics simulations.
We present a multi-laboratory effort to describe the structural and dynamical properties of duple... more We present a multi-laboratory effort to describe the structural and dynamical properties of duplex B-DNA under physiological conditions. By processing a large amount of atomistic molecular dynamics simulations, we determine the sequence-dependent structural properties of DNA as expressed in the equilibrium distribution of its stochastic dynamics. Our analysis includes a study of first and second moments of the equilibrium distribution, which can be accurately captured by a harmonic model, but with nonlocal sequence-dependence. We characterize the sequence-dependent choreography of backbone and base movements modulating the non-Gaussian or anharmonic effects manifested in the higher moments of the dynamics of the duplex when sampling the equilibrium distribution. Contrary to prior assumptions, such anharmonic deformations are not rare in DNA and can play a significant role in determining DNA conformation within complexes. Polymorphisms in helical geometries are particularly prevalent...
Summary veriNA3d is an R package for the analysis of nucleic acids structural data, with an empha... more Summary veriNA3d is an R package for the analysis of nucleic acids structural data, with an emphasis in complex RNA structures. In addition to single-structure analyses, veriNA3d also implements functions to handle whole datasets of mmCIF/PDB structures that could be retrieved from public/local repositories. Our package aims to fill a gap in the data mining of nucleic acids structures to produce flexible and high throughput analysis of structural databases. Availability and implementation http://mmb.irbbarcelona.org/gitlab/dgallego/veriNA3d. Supplementary information Supplementary data are available at Bioinformatics online.
DNA lesions caused by UV damage are thought to be repaired solely by the nucleotide excision repa... more DNA lesions caused by UV damage are thought to be repaired solely by the nucleotide excision repair (NER) pathway in human cells. Patients carrying mutations within genes functioning in this pathway display a range of pathologies, including an increased susceptibility to cancer, premature aging, and neurological defects. There are currently no curative therapies available. Here we performed a high-throughput chemical screen for agents that could alleviate the cellular sensitivity of NER-deficient cells to UV-induced DNA damage. This led to the identification of the clinically approved anti-diabetic drug acetohexamide, which promoted clearance of UV-induced DNA damage without the accumulation of chromosomal aberrations, hence promoting cellular survival. Acetohexamide exerted this protective function by antagonizing expression of the DNA glycosylase, MUTYH. Together, our data reveal the existence of an NER-independent mechanism to remove UV-induced DNA damage and prevent cell death.
The journal of physical chemistry. B, Apr 20, 2017
Extensive molecular dynamics (MD) simulations have been used to characterize the multiple roles o... more Extensive molecular dynamics (MD) simulations have been used to characterize the multiple roles of water in solvating different types of proteins under different environmental conditions. We analyzed a small set of proteins, representative of the most prevalent meta-folds under native conditions, in the presence of crowding agents, and at high temperature with or without high concentration of urea. We considered also a protein in the unfolded state as characterized by NMR and atomistic MD simulations. Our results outline the main characteristics of the hydration environment of proteins and illustrate the dramatic plasticity of water, and its chameleonic ability to stabilize proteins under a variety of conditions.
Protein conformational changes are at the heart of cell functions, from signalling to ion transpo... more Protein conformational changes are at the heart of cell functions, from signalling to ion transport. However, the transient nature of the intermediates along transition pathways hampers their experimental detection, making the underlying mechanisms elusive. Here we retrieve dynamic information on the actual transition routes from principal component analysis (PCA) of structurally-rich ensembles and, in combination with coarse-grained simulations, explore the conformational landscapes of five well-studied proteins. Modelling them as elastic networks in a hybrid elastic-network Brownian dynamics simulation (eBDIMS), we generate trajectories connecting stable end-states that spontaneously sample the crystallographic motions, predicting the structures of known intermediates along the paths. We also show that the explored non-linear routes can delimit the lowest energy passages between end-states sampled by atomistic molecular dynamics. The integrative methodology presented here provides...
The stability between helical conformations of homopeptides of alanine, glycine, and aminoisobuty... more The stability between helical conformations of homopeptides of alanine, glycine, and aminoisobutyric acid has been studied by means of quantum-mechanical methods. The influence of peptide length on the relative stability between helical conformations has also been analyzed by means of systematic studies for peptides of size up to 11 residues. Finally, the influence of the solvent has been examined by using self-consistent reaction field methods. The results provide a detailed picture of the modulation exerted by these factors on the helical preferences of these peptides.
Page 1. J. Mol. Model. 1996, 2, 1 -15 * To whom correspondence should be addressed Theoretical Me... more Page 1. J. Mol. Model. 1996, 2, 1 -15 * To whom correspondence should be addressed Theoretical Methods for the Representation of Solvent Modesto Orozco*, Cristobal Alhambra and Xavier Barril Departament de Bioquímica. Facultat de Química. Universitat de Barcelona. ...
Nucleosomes provide additional regulatory mechanisms to transcription and DNA replication by medi... more Nucleosomes provide additional regulatory mechanisms to transcription and DNA replication by mediating the access of proteins to DNA. During the cell cycle chromatin undergoes several conformational changes, however the functional significance of these changes to cellular processes are largely unexplored. Here, we present the first comprehensive genome-wide study of nucleosome plasticity at single base-pair resolution along the cell cycle in Saccharomyces cerevisiae. We determined nucleosome organization with a specific focus on two regulatory regions: transcription start sites (TSSs) and replication origins (ORIs). During the cell cycle, nucleosomes around TSSs display rearrangements in a cyclic manner. In contrast to gap (G1 and G2) phases, nucleosomes have a fuzzier organization during S and M phases, Moreover, the choreography of nucleosome rearrangements correlate with changes in gene expression during the cell cycle, indicating a strong association between nucleosomes and cell...
The Conserved Domain Database (CDD) is a compilation of multiple sequence alignments representing... more The Conserved Domain Database (CDD) is a compilation of multiple sequence alignments representing protein domains conserved in molecular evolution. It has been populated with alignment data from the public collections Pfam and SMART, as well as with contributions ...
ABSTRACTWe present a physics-based machine learning approach to predict in vitro transcription fa... more ABSTRACTWe present a physics-based machine learning approach to predict in vitro transcription factor binding affinities from structural and mechanical DNA properties directly derived from atomistic molecular dynamics simulations. The method is able to predict affinities obtained with techniques as different as uPBM, gcPBM and HT-SELEX with an excellent performance, much better than existing algorithms. Due to its nature, the method can be extended to epigenetic variants, mismatches, mutations, or any non-coding nucleobases. When complemented with chromatin structure information, our in vitro trained method provides also good estimates of in vivo binding sites in yeast.
Motivation The BioExcel Building Blocks (BioBB) library offers a broad collection of wrappers on ... more Motivation The BioExcel Building Blocks (BioBB) library offers a broad collection of wrappers on top of common biomolecular simulation and bioinformatics tools. The possibility to access the library remotely and programmatically increases its usability, allowing individual and sporadic executions and enabling remote workflows. Results BioBB REST API extends and complements the BioBB library offering programmatic access to the collection of biomolecular simulation tools included in the BioExcel Building Blocks library. Molecular Dynamics setup, docking, structure modeling, free energy simulations and flexibility analyses are examples of functionalities included in the endpoints collection. All functionalities are accessible through standard REST API calls, voiding the need for tool installation. Availability and implementation All the information related to the BioBB REST API endpoints is accessible from https://mmb.irbbarcelona.org/biobb-api/. Links to extended documentation, includ...
We have used a variety of theoretical and experimental techniques to study the role of four basic... more We have used a variety of theoretical and experimental techniques to study the role of four basic amino acids–Arginine, Lysine, Ornithine and L-2,4-Diaminobutyric acid–on the structure, flexibility and sequence-dependent stability of DNA. We found that the presence of organic ions stabilizes the duplexes and significantly reduces the difference in stability between AT- and GC-rich duplexes with respect to the control conditions. This suggests that these amino acids, ingredients of the primordial soup during abiogenesis, could have helped to equalize the stability of AT- and GC-rich DNA oligomers, facilitating a general non-catalysed self-replication of DNA. Experiments and simulations demonstrate that organic ions have an effect that goes beyond the general electrostatic screening, involving specific interactions along the grooves of the double helix. We conclude that organic ions, largely ignored in the DNA world, should be reconsidered as crucial structural elements far from mimic...
We present a new coarse grained method for the simulation of duplex DNA. The algorithm uses a gen... more We present a new coarse grained method for the simulation of duplex DNA. The algorithm uses a generalized multi-harmonic model that can represent any multi-normal distribution of helical parameters, thus avoiding caveats of current mesoscopic models for DNA simulation and representing a breakthrough in the field. The method has been parameterized from accurate parmbsc1 atomistic molecular dynamics simulations of all unique tetranucleotide sequences of DNA embedded in long duplexes and takes advantage of the correlation between helical states and backbone configurations to derive atomistic representations of DNA. The algorithm, which is implemented in a simple web interface and in a standalone package reproduces with high computational efficiency the structural landscape of long segments of DNA untreatable by atomistic molecular dynamics simulations.
We present a multi-laboratory effort to describe the structural and dynamical properties of duple... more We present a multi-laboratory effort to describe the structural and dynamical properties of duplex B-DNA under physiological conditions. By processing a large amount of atomistic molecular dynamics simulations, we determine the sequence-dependent structural properties of DNA as expressed in the equilibrium distribution of its stochastic dynamics. Our analysis includes a study of first and second moments of the equilibrium distribution, which can be accurately captured by a harmonic model, but with nonlocal sequence-dependence. We characterize the sequence-dependent choreography of backbone and base movements modulating the non-Gaussian or anharmonic effects manifested in the higher moments of the dynamics of the duplex when sampling the equilibrium distribution. Contrary to prior assumptions, such anharmonic deformations are not rare in DNA and can play a significant role in determining DNA conformation within complexes. Polymorphisms in helical geometries are particularly prevalent...
Summary veriNA3d is an R package for the analysis of nucleic acids structural data, with an empha... more Summary veriNA3d is an R package for the analysis of nucleic acids structural data, with an emphasis in complex RNA structures. In addition to single-structure analyses, veriNA3d also implements functions to handle whole datasets of mmCIF/PDB structures that could be retrieved from public/local repositories. Our package aims to fill a gap in the data mining of nucleic acids structures to produce flexible and high throughput analysis of structural databases. Availability and implementation http://mmb.irbbarcelona.org/gitlab/dgallego/veriNA3d. Supplementary information Supplementary data are available at Bioinformatics online.
DNA lesions caused by UV damage are thought to be repaired solely by the nucleotide excision repa... more DNA lesions caused by UV damage are thought to be repaired solely by the nucleotide excision repair (NER) pathway in human cells. Patients carrying mutations within genes functioning in this pathway display a range of pathologies, including an increased susceptibility to cancer, premature aging, and neurological defects. There are currently no curative therapies available. Here we performed a high-throughput chemical screen for agents that could alleviate the cellular sensitivity of NER-deficient cells to UV-induced DNA damage. This led to the identification of the clinically approved anti-diabetic drug acetohexamide, which promoted clearance of UV-induced DNA damage without the accumulation of chromosomal aberrations, hence promoting cellular survival. Acetohexamide exerted this protective function by antagonizing expression of the DNA glycosylase, MUTYH. Together, our data reveal the existence of an NER-independent mechanism to remove UV-induced DNA damage and prevent cell death.
The journal of physical chemistry. B, Apr 20, 2017
Extensive molecular dynamics (MD) simulations have been used to characterize the multiple roles o... more Extensive molecular dynamics (MD) simulations have been used to characterize the multiple roles of water in solvating different types of proteins under different environmental conditions. We analyzed a small set of proteins, representative of the most prevalent meta-folds under native conditions, in the presence of crowding agents, and at high temperature with or without high concentration of urea. We considered also a protein in the unfolded state as characterized by NMR and atomistic MD simulations. Our results outline the main characteristics of the hydration environment of proteins and illustrate the dramatic plasticity of water, and its chameleonic ability to stabilize proteins under a variety of conditions.
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Papers by Modesto Orozco