Elise Duboué-Dijon

Biomolecular hydration dynamics: a jump model perspective

The dynamics of water molecules within the hydration shell surrounding a biomolecule can have a crucial influence on its biochemical function. Characterizing their properties and the extent to which they differ from those of bulk water have thus been long-standing questions. Following a tutorial approach, we review the recent advances in this field and the different approaches which have probed the dynamical perturbation experienced by water in the vicinity of proteins or DNA. We discuss the molecular factors causing this perturbation, and describe how they change with temperature. We finally present more biologically relevant cases beyond the dilute aqueous situation. A special focus is on the jump model for water reorientation and hydrogen bond rearrangement.

Characterization of the Local Structure in Liquid Water by Various Order Parameters

A wide range of geometric order parameters have been suggested to characterize the local structure of liquid water and its tetrahedral arrangement, but their respective merits have remained elusive. Here, we consider a series of popular order parameters and analyze molecular dynamics simulations of water, in the bulk and in the hydration shell of a hydrophobic solute, at 298 and 260 K. We show that these parameters are weakly correlated and probe different distortions, for example the angular versus radial disorders. We first combine these complementary descriptions to analyze the structural rearrangements leading to the density maximum in liquid water. Our results reveal no sign of a heterogeneous mixture and show that the density maximum arises from the depletion in interstitial water molecules upon cooling. In the hydration shell of the hydrophobic moiety of propanol, the order parameters suggest that the water local structure is similar to that in the bulk, with only a very weak depletion in ordered configurations, thus confirming the absence of any iceberg-type structure. Finally, we show that the main structural fluctuations that affect water reorientation dynamics in the bulk are angular distortions, which we explain by the jump hydrogen-bond exchange mechanism.

Dynamical Disorder in the DNA Hydration Shell

The reorientation and hydrogen-bond dynamics of water molecules within the hydration shell of a B-DNA dodecamer, which are of interest for many of its biochemical functions, are investigated via molecular dynamics simulations and an analytic jump model, which provide valuable new molecular level insights into these dynamics. Different sources of heterogeneity in the hydration shell dynamics are determined. First, a pronounced spatial heterogeneity is found at the DNA interface and explained via the jump model by the diversity in local DNA interfacial topographies and DNA-water H-bond interactions. While most of the hydration shell is moderately retarded with respect to the bulk, some water molecules confined in the narrow minor groove exhibit very slow dynamics. An additional source of heterogeneity is found to be caused by the DNA conformational fluctuations, which modulate the water dynamics. The groove widening aids the approach of, and the jump to, a new water H-bond partner. This temporal heterogeneity is especially strong in the minor groove, where groove width fluctuations occur on the same time scale as the water H-bond rearrangements, leading to a strong dynamical disorder. The usual simplifying assumption that hydration shell dynamics is much faster than DNA dynamics is thus not valid; our results show that biomolecular conformational fluctuations are essential to facilitate the water motions and accelerate the hydration dynamics in confined groove sites.

Origins of the non-exponential reorientation dynamics of nanoconfined water

The 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.

Temperature dependence of hydrophobic hydration dynamics: from retardation to acceleration.

The perturbation induced by a hydrophobic solute on water dynamics is essential in many biochemical processes, but its mechanism and magnitude are still debated. A stringent test of the different proposed pictures is provided by recent NMR measurements by Qvist and Halle (J. Am. Chem. Soc. 2008, 130, 10345-10353) which showed that, unexpectedly, the perturbation changes in a non-monotonic fashion when the solution is cooled below room temperature. Here we perform and analyze molecular dynamics simulations of a small paradigm amphiphilic solute, trimethylamine N-oxide (TMAO), in dilute aqueous solutions over the 218-350 K temperature range. We first show that our simulations properly reproduce the non-monotonic temperature dependence. We then develop a model which combines our previously suggested entropic excluded-volume effect with a perturbation factor arising from the difference between local structural fluctuations in the shell and the bulk. Our model provides a detailed molecular understanding of the hydrophobic perturbation over the full temperature range investigated. It shows that the excluded-volume factor brings a dominant temperature-independent contribution to the perturbation at all temperatures, and provides a very good approximation at room temperature. The non-monotonic temperature dependence of the perturbation is shown to arise from the structural factor and mostly from relative shifts between the shell and bulk distributions of local structures, whose amplitude remains very small compared to the widths of those distributions.

Hydration and Ion Pairing in Aqueous Mg2+ and Zn2+ Solutions: Force-Field Description Aided by Neutron Scattering Experiments and Ab Initio Molecular Dynamics Simulations

Magnesium and zinc dications possess the same charge and have an almost identical size, yet they behave very differently in aqueous solutions and play distinct biological roles. It is thus crucial to identify the origins of such different behaviors and to assess to what extent they can be captured by force-field molecular dynamics simulations. In this work, we combine neutron scattering experiments in a specific mixture of H2O and D2O (the so-called null water) with ab initio molecular dynamics simulations to probe the difference in the hydration structure and ion-pairing properties of chloride solutions of the two cations. The obtained data are used as a benchmark to develop a scaled-charge force field for Mg2+ that includes electronic polarization in a mean field way. We show that using this electronic continuum correction we can describe aqueous magnesium chloride solutions well. However, in aqueous zinc chloride specific interaction terms between the ions need to be introduced to capture ion pairing quantitatively.

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

We present a combination of force field and ab initio molecular dynamics simulations together with neutron scattering experiments with isotopic substitution that aim at characterizing ion hydration and pairing in aqueous calcium chloride and formate/acetate solutions. Benchmarking against neutron scattering data on concentrated solutions together with ion pairing free energy profiles from ab initio molecular dynamics allows us to develop an accurate calcium force field which accounts in a mean-field way for electronic polarization effects via charge rescaling. This refined calcium parameterization is directly usable for standard molecular dynamics simulations of processes involving this key biological signaling ion.

Ab Initio Simulations of Water Dynamics in Aqueous TMAO Solutions: Temperature and Concentration Effects

We use ab initio molecular dynamics simulation to study the effect of hydrophobic groups on the dynamics of water molecules in aqueous solutions of trimethylamine N-oxide (TMAO). We show that hydrophobic groups induce a moderate (<2-fold) slowdown of water reorientation and hydrogen-bond dynamics in dilute solutions, but that this slowdown rapidly increases with solute concentration. In addition, the slowdown factor is found to vary very little with temperature, thus suggesting an entropic origin. All of these results are in quantitative agreement with prior classical molecular dynamics simulations and with the previously suggested excluded-volume model. The hydrophilic TMAO headgroup is found to affect water dynamics more strongly than the hydrophobic moiety, and the magnitude of this slowdown is very sensitive to the strength of the water-solute hydrogen-bond.

Coupled Valence-Bond State Molecular Dynamics Description of an Enzyme-Catalyzed Reaction in a Non-Aqueous Organic Solvent

Enzymes are widely used in nonaqueous solvents to catalyze non-natural reactions. While experimental measurements showed that the solvent nature has a strong effect on the reaction kinetics, the molecular details of the catalytic mechanism in nonaqueous solvents have remained largely elusive. Here we study the transesterification reaction catalyzed by the paradigm subtilisin Carlsberg serine protease in an organic apolar solvent. The rate-limiting acylation step involves a proton transfer between active-site residues and the nucleophilic attack of the substrate to form a tetrahedral intermediate. We design the first coupled valence-bond state model that simultaneously describes both reactions in the enzymatic active site. We develop a new systematic procedure to parametrize this model on high-level ab initio QM/MM free energy calculations that account for the molecular details of the active site and for both substrate and protein conformational fluctuations. Our calculations show that the reaction energy barrier changes dramatically with the solvent and protein conformational fluctuations. We find that the mechanism of the tetrahedral intermediate formation during the acylation step is similar to that determined under aqueous conditions, and that the proton transfer and nucleophilic attack reactions occur concertedly. We identify the reaction coordinate to be mostly due to the rearrangement of some residual water molecules close to the active site.

Binding of Divalent Cations to Insulin: Capillary Electrophoresis and Molecular Simulations

In the present study, we characterize the binding of divalent cations to insulin in aqueous salt solutions by means of capillary electrophoresis and molecular dynamics simulations. The results show a strong pH dependence. At low pH, at which all the carboxylate groups are protonated and the protein has an overall positive charge, all the cations exhibit only weak and rather unspecific interactions with insulin. In contrast, at close to neutral pH, when all the carboxylate groups are deprotonated and negatively charged, the charge-neutralizing effect of magnesium, calcium, and zinc, in particular, on the electrophoretic mobility of insulin is significant. This is also reflected in the results of molecular dynamics simulations showing accumulation of cations at the protein surface, which becomes smaller in magnitude upon effective inclusion of electronic polarization via charge rescaling.