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 suitability of the self-consistent reaction field (SCRF) strategy for the study of solutes in... more The suitability of the self-consistent reaction field (SCRF) strategy for the study of solutes in chloroform solution has been examined. The SCRF method developed by Miertus, Scrocco and Tomasi (MST) has been parametrized at both ab initio 6-31G* and semiempirical AM1, MNDO, and PM3 levels. The reliability of the MST/SCRF model has been assessed from the comparison with results derived from classical Monte Carlo-free energy perturbation simulations and from mixed Monte Carlo-quantum mechanical/molecular mechanical computations, as well as with experimental data. The parametrized MST/SCRF method estimates the free energy of solvation with a root-mean-square deviation of 0.4 kcal/mol from the experimental value for the molecules studied. Further confidence in the optimized method stems from its ability to reproduce the tautomeric change of 2-and 4-pyridone upon transfer from gas phase to chloroform and the partition coefficient for compounds not considered in the parametrization. The results indicate the suitability of the MST/SCRF model for the study of solvent effects in dilute chloroform solutions.
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.
The structure of noncovalent complexes of DNA duplex with minor groove binders (mG-binders) has b... more The structure of noncovalent complexes of DNA duplex with minor groove binders (mG-binders) has been analyzed by state of the art molecular dynamics (MD) simulations. More than 3.3 µs of MD trajectories (including 4 × 0.5 µs trajectories) were collected for the Dickerson's dodecamer bound to DAPI, Hoechst 33258, and Netropsin. Comparison of these trajectories with control simulations in water allowed us to determine that the extreme dehydration and partial neutralization occurring during electrospray experiments does not produce the disruption of the DNA:mG-binder complexes or the dissociation of the two strands of the duplex. Irrespective of the drug and the simulation conditions the mG-binders remains bound to the DNA near the preferential binding position in aqueous conditions. Large distortions appear in the two DNA strands, which maintain however a memory of the original DNA duplex structure in water, and a general helical-like conformation.
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. ...
While DNA is mostly a primary carrier of genetic information and displays a regular duplex struct... more While DNA is mostly a primary carrier of genetic information and displays a regular duplex structure, RNA can form very complicated and conserved 3D structures displaying a large variety of functions, such as being an intermediary carrier of the genetic information, translating such information into the protein machinery of the cell, or even acting as a chemical catalyst. At the base of such functional diversity is the subtle balance between different backbone, nucleobase, and ribose conformations, finely regulated by the combination of hydrogen bonds and stacking interactions. Although an apparently simple chemical modification, the presence of the 2'OH in RNA has a profound effect in the ribonucleotide conformational balance, adding an extra layer of complexity to the interactions network in RNA. In the present work, we have combined database analysis with extensive molecular dynamics, quantum mechanics, and hybrid QM/MM simulations to provide direct evidence on the dramatic impact of the 2'OH conformation on sugar puckering. Calculations provide evidence that proteins can modulate the 2'OH conformation to drive sugar repuckering, leading then to the formation of bioactive conformations. In summary, the 2'OH group seems to be a primary molecular switch contributing to specific protein-RNA recognition.
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 ...
The linear sequence of DNA provides invaluable information about genes and their regulatory eleme... more The linear sequence of DNA provides invaluable information about genes and their regulatory elements along chromosomes. However, to fully understand gene function and regulation, we need to dissect how genes physically fold in the three-dimensional nuclear space. Here we describe immuno-OligoSTORM, an imaging strategy that reveals the distribution of nucleosomes within specific genes in super-resolution, through the simultaneous visualization of DNA and histones. We combine immuno-OligoSTORM with restraint-based and coarse-grained modeling approaches to integrate super-resolution imaging data with Hi-C contact frequencies and deconvoluted micrococcal nuclease-sequencing information. The resulting method, called Modeling immuno-OligoSTORM, allows quantitative modeling of genes with nucleosome resolution and provides information about chromatin accessibility for regulatory factors, such as RNA polymerase II. With Modeling immuno-OligoSTORM, we explore intercellular variability, transcriptional-dependent gene conformation, and folding of housekeeping and pluripotency-related genes in human pluripotent and differentiated cells, thereby obtaining the highest degree of data integration achieved so far to our knowledge. Unraveling the three-dimensional (3D) genome organization of chromatin fiber is paramount to understanding gene function. In recent years, important advances have been made through the use of genomic approaches, mainly chromosome conformation capture (3C)-based techniques, such as Hi-C, ChIA-PET and Micro-C, among others 1-3 . Obtaining 3D spatial organization of chromosomes and identifying proximal chromatin interactions between different genomic regions has greatly advanced our understanding of gene regulation. Chromosomes have been shown to segregate into specific nuclear regions, called chromosome territories, as well as into heterochromatin and euchromatin, which are partitioned in A and B compartments 4 . Topologically associated domains (TADs) 5-8 and loops 9 further subdivide the chromatin fiber 10 .
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 suitability of the self-consistent reaction field (SCRF) strategy for the study of solutes in... more The suitability of the self-consistent reaction field (SCRF) strategy for the study of solutes in chloroform solution has been examined. The SCRF method developed by Miertus, Scrocco and Tomasi (MST) has been parametrized at both ab initio 6-31G* and semiempirical AM1, MNDO, and PM3 levels. The reliability of the MST/SCRF model has been assessed from the comparison with results derived from classical Monte Carlo-free energy perturbation simulations and from mixed Monte Carlo-quantum mechanical/molecular mechanical computations, as well as with experimental data. The parametrized MST/SCRF method estimates the free energy of solvation with a root-mean-square deviation of 0.4 kcal/mol from the experimental value for the molecules studied. Further confidence in the optimized method stems from its ability to reproduce the tautomeric change of 2-and 4-pyridone upon transfer from gas phase to chloroform and the partition coefficient for compounds not considered in the parametrization. The results indicate the suitability of the MST/SCRF model for the study of solvent effects in dilute chloroform solutions.
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.
The structure of noncovalent complexes of DNA duplex with minor groove binders (mG-binders) has b... more The structure of noncovalent complexes of DNA duplex with minor groove binders (mG-binders) has been analyzed by state of the art molecular dynamics (MD) simulations. More than 3.3 µs of MD trajectories (including 4 × 0.5 µs trajectories) were collected for the Dickerson's dodecamer bound to DAPI, Hoechst 33258, and Netropsin. Comparison of these trajectories with control simulations in water allowed us to determine that the extreme dehydration and partial neutralization occurring during electrospray experiments does not produce the disruption of the DNA:mG-binder complexes or the dissociation of the two strands of the duplex. Irrespective of the drug and the simulation conditions the mG-binders remains bound to the DNA near the preferential binding position in aqueous conditions. Large distortions appear in the two DNA strands, which maintain however a memory of the original DNA duplex structure in water, and a general helical-like conformation.
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. ...
While DNA is mostly a primary carrier of genetic information and displays a regular duplex struct... more While DNA is mostly a primary carrier of genetic information and displays a regular duplex structure, RNA can form very complicated and conserved 3D structures displaying a large variety of functions, such as being an intermediary carrier of the genetic information, translating such information into the protein machinery of the cell, or even acting as a chemical catalyst. At the base of such functional diversity is the subtle balance between different backbone, nucleobase, and ribose conformations, finely regulated by the combination of hydrogen bonds and stacking interactions. Although an apparently simple chemical modification, the presence of the 2'OH in RNA has a profound effect in the ribonucleotide conformational balance, adding an extra layer of complexity to the interactions network in RNA. In the present work, we have combined database analysis with extensive molecular dynamics, quantum mechanics, and hybrid QM/MM simulations to provide direct evidence on the dramatic impact of the 2'OH conformation on sugar puckering. Calculations provide evidence that proteins can modulate the 2'OH conformation to drive sugar repuckering, leading then to the formation of bioactive conformations. In summary, the 2'OH group seems to be a primary molecular switch contributing to specific protein-RNA recognition.
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 ...
The linear sequence of DNA provides invaluable information about genes and their regulatory eleme... more The linear sequence of DNA provides invaluable information about genes and their regulatory elements along chromosomes. However, to fully understand gene function and regulation, we need to dissect how genes physically fold in the three-dimensional nuclear space. Here we describe immuno-OligoSTORM, an imaging strategy that reveals the distribution of nucleosomes within specific genes in super-resolution, through the simultaneous visualization of DNA and histones. We combine immuno-OligoSTORM with restraint-based and coarse-grained modeling approaches to integrate super-resolution imaging data with Hi-C contact frequencies and deconvoluted micrococcal nuclease-sequencing information. The resulting method, called Modeling immuno-OligoSTORM, allows quantitative modeling of genes with nucleosome resolution and provides information about chromatin accessibility for regulatory factors, such as RNA polymerase II. With Modeling immuno-OligoSTORM, we explore intercellular variability, transcriptional-dependent gene conformation, and folding of housekeeping and pluripotency-related genes in human pluripotent and differentiated cells, thereby obtaining the highest degree of data integration achieved so far to our knowledge. Unraveling the three-dimensional (3D) genome organization of chromatin fiber is paramount to understanding gene function. In recent years, important advances have been made through the use of genomic approaches, mainly chromosome conformation capture (3C)-based techniques, such as Hi-C, ChIA-PET and Micro-C, among others 1-3 . Obtaining 3D spatial organization of chromosomes and identifying proximal chromatin interactions between different genomic regions has greatly advanced our understanding of gene regulation. Chromosomes have been shown to segregate into specific nuclear regions, called chromosome territories, as well as into heterochromatin and euchromatin, which are partitioned in A and B compartments 4 . Topologically associated domains (TADs) 5-8 and loops 9 further subdivide the chromatin fiber 10 .
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