Computer Simulation and Modeling Laboratory

Eixample, Spain

Computer Simulation and Modeling Laboratory

Eixample, Spain
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Biarnes X.,Computer Simulation and Modeling Laboratory | Biarnes X.,Ramon Llull University | Ardevol A.,Institute Of Quimica Teorica I Computacional Of La Ub | Ardevol A.,Computer Simulation and Modeling Laboratory | And 6 more authors.
Journal of the American Chemical Society | Year: 2011

Retaining glycoside hydrolases (GHs), key enzymes in the metabolism of polysaccharides and glycoconjugates and common biocatalysts used in chemoenzymatic oligosaccharide synthesis, operate via a double-displacement mechanism with the formation of a glycosyl-enzyme intermediate. However, the degree of oxocarbenium ion character of the reaction transition state and the precise conformational itinerary of the substrate during the reaction, pivotal in the design of efficient inhibitors, remain elusive for many GHs. By means of QM/MM metadynamics, we unravel the catalytic itinerary of 1,3-1,4-β- glucanase, one of the most active GHs, belonging to family 16. We show that, in the Michaelis complex, the enzyme environment restricts the conformational motion of the substrate to stabilize a 1,4B/1S3 conformation of the saccharide ring at the -1 subsite, confirming that this distortion preactivates the substrate for catalysis. The metadynamics simulation of the enzymatic reaction captures the complete conformational itinerary of the substrate during the glycosylation reaction (1,4B/1S 3 -4E/4H3 - 4C 1) and shows that the transition state is not the point of maximum charge development at the anomeric carbon. The overall catalytic mechanism is of dissociative type, and proton transfer to the glycosidic oxygen is a late event, clarifying previous kinetic studies of this enzyme. © 2011 American Chemical Society.


Rojas-Cervellera V.,Computer Simulation and Modeling Laboratory | Rojas-Cervellera V.,Institute Of Quimica Teorica I Computacional | Rojas-Cervellera V.,University of Barcelona | Giralt E.,Institute Of Recerca Biomedica Of Barcelona | And 5 more authors.
Inorganic Chemistry | Year: 2012

Recent structural determinations have shown that thiolate-protected gold nanoparticles are not as regular and symmetric as initially thought, but characteristic substructures (staple motifs) are formed on their surface. However, their mechanism of formation, especially the fate of the sulfur protons upon thiol binding, remains one of the most intriguing unanswered questions in gold cluster chemistry. By means of ab initio molecular dynamics (AIMD), we monitor the trajectory of thiol protons reacting with a gold cluster, demonstrating that the staple motif forms in a multiple-pathway chemical reaction, releasing molecular hydrogen. The results obtained also reconcile the conclusions of structural determinations with the interpretations of spectroscopic experiments on solution, suggesting the presence of intact thiols or chemisorbed hydrogen. © 2012 American Chemical Society.


Biarns X.,Computer Simulation and Modeling Laboratory | Biarns X.,International School for Advanced Studies | Ardvol A.,Computer Simulation and Modeling Laboratory | Ardvol A.,Institute Of Qumica Terica I Computacional Iqtcub | And 4 more authors.
Biocatalysis and Biotransformation | Year: 2010

A current issue in the understanding of β-glycoside hydrolase (β-GH) mechanisms is the conformational itinerary that the substrate follows during the reaction, in which substrate distortion is induced upon binding to the enzyme. The precise knowledge of the structure of the Michaelis complex, the covalent intermediate (in the case of retaining GHs) or the product gives hints on how to predict the transition state structures and this has an impact on the design of inhibitors for these enzymes. Here we summarize our recent work on substrate distortion in GHs using first-principles molecular dynamics. First, we show that distortion of the substrate is required for binding to 1,3-1,4-β-glucanase, a family 16 GH, and that this distortion results in electronic and structural changes in the substrate that favor cleavage of the glycosidic bond. Second, by analyzing the conformational energy landscape of β-D-glucopyranose, we demonstrate that the most stable distorted conformations (1S5, 1,4B, 1S3, B3,o, 2SO and 2,5B) are pre-activated for catalysis in terms of small structural and electronic changes around the anomeric carbon. These conformations are the ones found in Michaelis complexes of GHs, suggesting that enzymesubstrate interactions have evolved to use these properties for efficient catalysis. © 2010 Informa UK Ltd.


Unno M.,Tohoku University | Unno M.,Ibaraki University | Unno M.,RIKEN | Ardevol A.,Computer Simulation and Modeling Laboratory | And 4 more authors.
Journal of Biological Chemistry | Year: 2013

Heme oxygenase catalyzes the degradation of heme to biliverdin, iron, and carbon monoxide. Here, we present crystal structures of the substrate-free, Fe3+-biliverdin-bound, and biliverdin-bound forms of HmuO, a heme oxygenase from Corynebacterium diphtheriae, refined to 1.80, 1.90, and 1.85Å resolution, respectively. In the substrate-free structure, the proximal and distal helices, which tightly bracket the substrate heme in the substrate-bound heme complex, move apart, and the proximal helix is partially unwound. These features are supported by the molecular dynamic simulations. The structure implies that the heme binding fixes the enzyme active site structure, including the water hydrogen bond network critical for heme degradation. The biliverdin groups assume the helical conformation and are located in the heme pocket in the crystal structures of the Fe3+-biliverdin-bound and the biliverdinbound HmuO, prepared by in situ heme oxygenase reaction from the heme complex crystals. The proximal His serves as the Fe3+-biliverdin axial ligand in the former complex and forms a hydrogen bond through a bridging water molecule with the biliverdin pyrrole nitrogen atoms in the latter complex. In both structures, salt bridges between one of the biliverdin propionate groups and the Arg and Lys residues further stabilize biliverdin at theHmuOheme pocket. Additionally, the crystal structure of a mixture of two intermediates between the Fe3+-biliverdin and biliverdin complexes has been determined at 1.70Å resolution, implying a possible route for iron exit. © 2013 by The American Society for Biochemistry and Molecular Biology, Inc.


Thompson A.J.,University of York | Dabin J.,University of York | Iglesias-Fernandez J.,Computer Simulation and Modeling Laboratory | Iglesias-Fernandez J.,Institute Of Quimica Tearica I Computacional Iqtcub | And 17 more authors.
Angewandte Chemie - International Edition | Year: 2012

Mannosides in the southern hemisphere: Conformational analysis of enzymatic mannoside hydrolysis informs strategies for enzyme inhibition and inspires solutions to mannoside synthesis. Atomic resolution structures along the reaction coordinate of an inverting α-mannosidase show how the enzyme distorts the substrate and transition state. QM/MM calculations reveal how the free energy landscape of isolated α-D-mannose is molded on enzyme to only allow one conformationally accessible reaction coordinate. Copyright © 2012 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.


Cantu D.C.,Iowa State University | Ardevol A.,Computer Simulation and Modeling Laboratory | Ardevol A.,ETH Zurich | Rovira C.,University of Barcelona | And 2 more authors.
Chemistry - A European Journal | Year: 2014

Thioesterases are enzymes that hydrolyze thioester bonds between a carbonyl group and a sulfur atom. They catalyze key steps in fatty acid biosynthesis and metabolism, as well as polyketide biosynthesis. The reaction molecular mechanism of most hotdog-fold acyl-CoA thioesterases remains unknown, but several hypotheses have been put forward in structural and biochemical investigations. The reaction of a human thioesterase (hTHEM2), representing a thioesterase family with a hotdog fold where a coenzymeA moiety is cleaved, was simulated by quantum mechanics/molecular mechanics metadynamics techniques to elucidate atomic and electronic details of its mechanism, its transition-state conformation, and the free energy landscape of the process. A single-displacement acid-base-like mechanism, in which a nucleophilic water molecule is activated by an aspartate residue acting as a base, was found, confirming previous experimental proposals. The results provide unambiguous evidence of the formation of a tetrahedral-like transition state. They also explain the roles of other conserved active-site residues during the reaction, especially that of a nearby histidine/serine pair that protonates the thioester sulfur atom, the participation of which could not be elucidated from mutation analyses alone. The mechanics of a hotdog-fold thioesterase: The reaction of a human thioesterase was simulated by quantum mechanics/molecular mechanics metadynamics techniques to elucidate atomic and electronic details of its mechanism, its transition-state conformation, and the free energy landscape of the process. The results provide unambiguous evidence of the formation of a tetrahedral-like transition state (indicated as TS on the free-energy surface reconstructed from the metadynamics simulation). © 2014 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.


Saade M.,Institute Biologia Molecular Of Barcelona | Gutierrez-Vallejo I.,Institute Biologia Molecular Of Barcelona | LeDreau G.,Institute Biologia Molecular Of Barcelona | Rabadan M.A.,Institute Biologia Molecular Of Barcelona | And 3 more authors.
Cell Reports | Year: 2013

The different modes of stem cell division are tightly regulated to balance growth and differentiation during organ development and homeostasis, and these regulatory processes are subverted in tumor formation. Here, we developed markers that provided the single-cell resolution necessary to quantify the three modes of division taking place in the developing nervous system invivo: self-expanding, PP; self-replacing, PN; and self-consuming, NN. Using these markers and a mathematical model that predicts the dynamics of motor neuron progenitor division, we identify a role for the morphogen Sonic hedgehog in the maintenance of stem cell identity in the developing spinal cord. Moreover, our study provides insight into the process linking lineage commitment to neurogenesis with changes in cell-cycle parameters. As a result, we propose a challenging model in which the external Sonic hedgehog signal dictates stem cell identity, reflected in the consequent readjustment of cell-cycle parameters


Alfonso-Prieto M.,Computer Simulation and Modeling Laboratory | Alfonso-Prieto M.,Temple University | Oberhofer H.,University of Cambridge | Klein M.L.,Temple University | And 4 more authors.
Journal of the American Chemical Society | Year: 2011

Heme catalases prevent cells from oxidative damage by decomposing hydrogen peroxide into water and molecular oxygen. Here we investigate the factors that give rise to an undesirable side reaction competing with normal catalase activity, the migration of a radical from the heme active site to the protein in the principal reaction intermediate compound I (Cpd I). Recently, it has been proposed that this electron transfer reaction takes place in Cpd I of Helicobacter pylori catalase (HPC), but not in Cpd I of Penicillium vitale catalase (PVC), where the oxidation equivalent remains located on the heme active site. Unraveling the factors determining the different radical locations could help engineer enzymes with enhanced catalase activity for detection or removal of hydrogen peroxide. Using quantum mechanics/molecular mechanics metadynamics simulations, we show that radical migration in HPC is facilitated by the large driving force (-0.65 eV) of the subsequent proton transfer from a histidine residue to the ferryl oxygen atom of reduced Cpd I. The corresponding free energy in PVC is significantly smaller (-0.19 eV) and, as we argue, not sufficiently high to support radical migration. Our results suggest that the energetics of oxoferryl protonation is a key factor regulating radical migration in catalases and possibly also in hydroperoxidases. © 2011 American Chemical Society.


Oriol C.-X.,Computer Simulation and Modeling Laboratory | Sagues F.,University of Barcelona | Buceta J.,Computer Simulation and Modeling Laboratory
Biophysical Journal | Year: 2010

Herein we report on the effects that different stochastic contributions induce in bacterial colonies in terms of protein concentration and production. In particular, we consider for what we believe to be the first time cell-to-cell diversity due to the unavoidable randomness of the cell-cycle duration and its interplay with other noise sources. To that end, we model a recent experimental setup that implements a protein dilution protocol by means of division events to characterize the gene regulatory function at the single cell level. This approach allows us to investigate the effect of different stochastic terms upon the total randomness experimentally reported for the gene regulatory function. In addition, we show that the interplay between intrinsic fluctuations and the stochasticity of the cell-cycle duration leads to different constructive roles. On the one hand, we show that there is an optimal value of protein concentration (alternatively an optimal value of the cell cycle phase) such that the noise in protein concentration attains a minimum. On the other hand, we reveal that there is an optimal value of the stochasticity of the cell cycle duration such that the coherence of the protein production with respect to the colony average production is maximized. The latter can be considered as a novel example of the recently reported phenomenon of diversity induced resonance. © 2010 by the Biophysical Society.


PubMed | Computer Simulation and Modeling Laboratory
Type: Journal Article | Journal: Inorganic chemistry | Year: 2012

Recent structural determinations have shown that thiolate-protected gold nanoparticles are not as regular and symmetric as initially thought, but characteristic substructures (staple motifs) are formed on their surface. However, their mechanism of formation, especially the fate of the sulfur protons upon thiol binding, remains one of the most intriguing unanswered questions in gold cluster chemistry. By means of ab initio molecular dynamics (AIMD), we monitor the trajectory of thiol protons reacting with a gold cluster, demonstrating that the staple motif forms in a multiple-pathway chemical reaction, releasing molecular hydrogen. The results obtained also reconcile the conclusions of structural determinations with the interpretations of spectroscopic experiments on solution, suggesting the presence of intact thiols or chemisorbed hydrogen.

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