Hydration and Ion Pairing in Aqueous Mg 2+ and Zn 2+ Solutions: Force-Field Description Aided by Neutron Scattering Experiments and Ab Initio Molecular Dynamics Simulations

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Changes in the hydration structure of imidazole upon protonation: Neutron scattering and molecular simulations

International audienceThe imidazole motif is widely encountered in biomolecules, and its biological role, for instance as a proton relay, is often linked to its ability to form hydrogen bonds with water molecules. Detailed characterization of the hydration pattern of imidazole and its changes upon protonation is thus of high interest. Here, we combine neutron scattering experiments with force field simulations to provide an unprecedented characterization of the neutral and protonated imidazole solvation at the atomistic level. We show that neutron diffraction data can be used to assess the quality of the imidazole force field in molecular simulations. Simulations using the CHARMM general force field for imidazole are in excellent agreement with the experimental neutron scattering data and we use them to provide an atomic scale interpretation of the neutron scattering patterns. Upon protonation, we clearly identify the signature of the reorganization in the hydration pattern caused by the change from one H-bond donor and one H-bond acceptor group for imidazole to two H-bond donor groups for imidazolium. We also point the limits of the experiment, which is rather insensitive to details of the H-bond geometry at the deprotonated nitrogen of imidazole and further complement the description of the hydration structure with ab initio molecular dynamics simulations

Hydration of biologically relevant tetramethylammonium cation by neutron scattering and molecular dynamics

Neutron scattering and molecular dynamics studies were performed on a concentrated aqueous tetramethylammonium (TMA) chloride solution to gain insight into the hydration shell structure of TMA, which is relevant for understanding its behavior in biological contexts of, e.g., properties of phospholipid membrane headgroups or interactions between DNA and histones. Specifically, neutron diffraction with isotopic substitution experiments were performed on TMA and water hydrogens to extract the specific correlation between hydrogens in TMA ($\mathrm{H_{TMA}}$) and hydrogens in water ($\mathrm{H_{W}}$). Classical molecular dynamics simulations were performed to help interpret the experimental neutron scattering data. Comparison of the hydration structure and simulated neutron signals obtained with various force field flavors (e.g. overall charge, charge distribution, polarity of the CH bonds and geometry) allowed us to gain insight into how sensitive the TMA hydration structure is to such changes and how much the neutron signal can capture them. We show that certain aspects of the hydration, such as the correlation of the hydrogen on TMA to hydrogen on water, showed little dependence on the force field. In contrast, other correlations, such as the ion-ion interactions, showed more marked changes. Strikingly, the neutron scattering signal cannot discriminate between different hydration patterns. Finally, ab initio molecular dynamics was used to examine the three-dimensional hydration structure and thus to benchmark force field simulations. Overall, while neutron scattering has been previously successfully used to improve force fields, in the particular case of TMA we show that it has only limited value to fully determine the hydration structure, with other techniques such as ab initio MD being of a significant help

Origins of the non-exponential reorientation dynamics of nanoconfined water

This is the published version. Copyright 2014 American Institute of PhysicsThe dynamics of water are dramatically modified upon confinement in nanoscale hydrophilic silica pores. In particular, the OH reorientation dynamics of the interfacial water are non-exponential and dramatically slowed relative to the bulk liquid. A detailed analysis of molecular dynamics simulations is carried out to elucidate the microscopic origins of this behavior. The results are analyzed in the context of the extended jump model for water that describes the reorientation as a combination of hydrogen-bond exchanges, or jumps, and rotation of intact hydrogen bonds, with the former representing the dominant contribution. Within this model, the roles of surface and dynamical heterogeneities are considered by spatially resolving the hydrogen-bond jump dynamics into individual sites on the silica pore surface. For each site the dynamics is nearly mono-exponential, indicating that dynamical heterogeneity is at most a minor influence, while the distribution of these individual site jump times is broad. The non-exponential dynamics can also not be attributed to enthalpic contributions to the barriers to hydrogen-bond exchanges. Two entropic effects related to the surface roughness are found to explain the retarded and diverse dynamics: those associated with the approach of a new hydrogen-bond acceptor and with the breaking of the initial hydrogen-bond

Calcium ions in aqueous solutions: Accurate force field description aided by ab initio molecular dynamics and neutron scattering

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Can Arginine Inhibit Insulin Aggregation? A Combined Protein Crystallography, Capillary Electrophoresis, and Molecular Simulation Study

The oligomeric state of the storage form of human insulin in the pancreas, which may be affected by several endogenous components of β-cell storage granules such as arginine, is not known. Here, the effect of arginine on insulin oligomerization is investigated independently by protein crystallography, molecular dynamics simulations, and capillary electrophoresis. The combined results point to a strong effect of ionic strength on insulin assembly. Molecular simulations and electrophoretic measurements at low/mM salt concentrations show no significant effect of arginine on insulin aggregation. In contrast, crystallographic data at high/molar ionic strength indicate inhibition of insulin hexamerization by arginine due to its binding at the site relevant for intermolecular contacts, which was also observed in MD simulations. Our results thus bracket the in vivo situation in pancreatic β-cell storage granules, where the ionic strength is estimated to be in the hundreds of millimolar to submolar range. The present findings add to a molecular understanding of in vivo insulin oligomerization and storage, with additional implications for insulin stability in arginine-rich injections

Ultrafast Vibrational Spectroscopy of Aqueous Solution of Methylamine from First Principles MD Simulations

We performed Car-Parrinello molecular dynamics (CPMD) simulations of deuterated aqueous solution of methylamine (MA) to investigate the structure, dynamics and time dependent vibrational spectra of water molecules in the first solvation shell. Our results show that the hydrogen bond of DOD…ND2 is the dominant interaction between ND2 and D2O as compared to the D2O…D2N. The hydrogen bond involving DOD…ND2 has longer lifetime (2.6 ps) than both D2O…D2N (1.1 ps) and water-water hydrogen bonds. The residence time of water molecule inside the first solvation shell of ND2 is 5.72 ps. The vibrational spectral diffusion of water molecules in the first hydration shell of the amine nitrogen of methylamine proceeds with three time scales. A short-time relaxation originates from dynamics of amine-water hydrogen bonds without breaking (90 fs), and a slower relaxation (∼1.8 ps) is due to the breaking of amine-water hydrogen bonds. Another longer time constant (∼7 ps) is due to the escape dynamics of water molecules from the first hydration shell of the amine group

Interactions entre une biomolécule et son environnement : de la dynamique d'hydratation à la catalyse enzymatique

Biomolecules are immersed in an aqueous solvent, which plays a key role in a wide range of biochemical processes. In addition, the properties of water molecules in the hydration shell are perturbed by the presence of the biomolecule. In this thesis, we combine theoretical models and numerical simulations to provide a molecular description of the interplay between a biomolecule and its environment. The manuscript is structured in two parts, addressing two complementary aspects of this complex interaction. In the first part we focus on the perturbation induced by a biomolecule on water molecules. We determine how much the hydration shell differs from bulk water and we identify the molecular factors at play. We then compare the hydration shells of an antifreeze protein and of a typical protein and investigate whether the shell structure and dynamics can explain the antifreeze properties. We finally study the hydration dynamics of a DNA dodecamer where slow water dynamics was suggested. We obtain a spatially resolved picture of DNA hydration and investigate the sources of heterogeneity. In the second part we examine the role of the environment in the chemical step of enzyme catalysis. We focus on two distinct systems with different questions, but relying on a common simulation methodology. We first examine the role of specific active site residues in catalysis by dihydrofolate reductase and we provide a molecular interpretation of recent experimental results. We finally study the role of water in enzyme catalysis in organic solvents, where addition of small amounts of water was shown to accelerate the chemical step. We seek a molecular scale description of this effect.Les biomolécules sont naturellement immergées dans l’eau, qui joue un rôle clé dans de nombreux processus biologiques. Réciproquement, les propriétés de l’eau sont affectées par la présence de la biomolécule. Dans cette thèse, nous combinons modèles théoriques et simulations numériques pour obtenir une description à l’échelle moléculaire des interactions entre une biomolécule et son environnement. Le manuscrit est structuré en deux parties, abordant deux aspects complémentaires de cette interaction complexe. La première partie est consacrée à la perturbation induite par une biomolécule sur l’eau. Nous déterminons en quoi la couche d’hydratation diffère de l’eau bulk et identifions les facteurs moléculaires en jeu. Nous comparons ensuite les couches d’hydratation d’une protéine antigel et d’une protéine modèle afin de déterminer si les propriétés d’hydratation peuvent expliquer l’activité antigel. Nous étudions enfin la dynamique d’hydratation de l’ADN. Nous obtenons une image résolue spatialement des propriétés de sa couche d’hydratation et y caractérisons les différentes sources d’hétérogénéité. La deuxième partie s’intéresse au rôle de l’environnement sur la catalyse enzymatique. Nous étudions deux systèmes distincts, avec des questions différentes mais une même méthodologie. Nous examinons d’abord le rôle de résidus dans le site actif de la dihydrofolate réductase et obtenons une interprétation moléculaire de résultats expérimentaux récents. Enfin, nous nous intéressons à la catalyse enzymatique en solvant organique, où l’addition de petites quantités d’eau permet d’accélérer la réaction. Nous recherchons une description à l’échelle moléculaire de cet effet

Interplay between a biomolecule and its environment : from hydration dynamics to enzyme catalysis

Les biomolécules sont naturellement immergées dans l’eau, qui joue un rôle clé dans de nombreux processus biologiques. Réciproquement, les propriétés de l’eau sont affectées par la présence de la biomolécule. Dans cette thèse, nous combinons modèles théoriques et simulations numériques pour obtenir une description à l’échelle moléculaire des interactions entre une biomolécule et son environnement. Le manuscrit est structuré en deux parties, abordant deux aspects complémentaires de cette interaction complexe. La première partie est consacrée à la perturbation induite par une biomolécule sur l’eau. Nous déterminons en quoi la couche d’hydratation diffère de l’eau bulk et identifions les facteurs moléculaires en jeu. Nous comparons ensuite les couches d’hydratation d’une protéine antigel et d’une protéine modèle afin de déterminer si les propriétés d’hydratation peuvent expliquer l’activité antigel. Nous étudions enfin la dynamique d’hydratation de l’ADN. Nous obtenons une image résolue spatialement des propriétés de sa couche d’hydratation et y caractérisons les différentes sources d’hétérogénéité. La deuxième partie s’intéresse au rôle de l’environnement sur la catalyse enzymatique. Nous étudions deux systèmes distincts, avec des questions différentes mais une même méthodologie. Nous examinons d’abord le rôle de résidus dans le site actif de la dihydrofolate réductase et obtenons une interprétation moléculaire de résultats expérimentaux récents. Enfin, nous nous intéressons à la catalyse enzymatique en solvant organique, où l’addition de petites quantités d’eau permet d’accélérer la réaction. Nous recherchons une description à l’échelle moléculaire de cet effet.Biomolecules are immersed in an aqueous solvent, which plays a key role in a wide range of biochemical processes. In addition, the properties of water molecules in the hydration shell are perturbed by the presence of the biomolecule. In this thesis, we combine theoretical models and numerical simulations to provide a molecular description of the interplay between a biomolecule and its environment. The manuscript is structured in two parts, addressing two complementary aspects of this complex interaction. In the first part we focus on the perturbation induced by a biomolecule on water molecules. We determine how much the hydration shell differs from bulk water and we identify the molecular factors at play. We then compare the hydration shells of an antifreeze protein and of a typical protein and investigate whether the shell structure and dynamics can explain the antifreeze properties. We finally study the hydration dynamics of a DNA dodecamer where slow water dynamics was suggested. We obtain a spatially resolved picture of DNA hydration and investigate the sources of heterogeneity. In the second part we examine the role of the environment in the chemical step of enzyme catalysis. We focus on two distinct systems with different questions, but relying on a common simulation methodology. We first examine the role of specific active site residues in catalysis by dihydrofolate reductase and we provide a molecular interpretation of recent experimental results. We finally study the role of water in enzyme catalysis in organic solvents, where addition of small amounts of water was shown to accelerate the chemical step. We seek a molecular scale description of this effect

Comparative study of hydration shell dynamics around a hyperactive antifreeze protein and around ubiquitin

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