How proteins modify water dynamics.

Filip Persson,Bertil Halle,Pär Söderhjelm

doi:10.1063/1.5026861

Abstract

Much of biology happens at the protein-water interface, so all dynamical processes in this region are of fundamental importance. Local structural fluctuations in the hydration layer can be probed by 17O magnetic relaxation dispersion (MRD), which, at high frequencies, measures the integral of a biaxial rotational time correlation function (TCF)-the integral rotational correlation time. Numerous 17O MRD studies have demonstrated that this correlation time, when averaged over the first hydration shell, is longer than in bulk water by a factor 3-5. This rotational perturbation factor (RPF) has been corroborated by molecular dynamics simulations, which can also reveal the underlying molecular mechanisms. Here, we address several outstanding problems in this area by analyzing an extensive set of molecular dynamics data, including four globular proteins and three water models. The vexed issue of polarity versus topography as the primary determinant of hydration water dynamics is resolved by establishing a protein-invariant exponential dependence of the RPF on a simple confinement index. We conclude that the previously observed correlation of the RPF with surface polarity is a secondary effect of the correlation between polarity and confinement. Water rotation interpolates between a perturbed but bulk-like collective mechanism at low confinement and an exchange-mediated orientational randomization (EMOR) mechanism at high confinement. The EMOR process, which accounts for about half of the RPF, was not recognized in previous simulation studies, where only the early part of the TCF was examined. Based on the analysis of the experimentally relevant TCF over its full time course, we compare simulated and measured RPFs, finding a 30% discrepancy attributable to force field imperfections. We also compute the full 17O MRD profile, including the low-frequency dispersion produced by buried water molecules. Computing a local RPF for each hydration shell, we find that the perturbation decays exponentially with a decay "length" of 0.3 shells and that the second and higher shells account for a mere 3% of the total perturbation measured by 17O MRD. The only long-range effect is a weak water alignment in the electric field produced by an electroneutral protein (not screened by counterions), but this effect is negligibly small for 17O MRD. By contrast, we find that the 17O TCF is significantly more sensitive to the important short-range perturbations than the other two TCFs examined here.

Highlights

The dynamics of the protein-water interface is of fundamental importance for many biological processes
Once the MHz frequency dependence had been causally linked to buried water molecules,15 it became clear that 17O magnetic relaxation dispersion (MRD) provides, in addition to information about the buried water molecules, a model-independent global measure of water dynamics in the external hydration shell: the shell-averaged integral rotational correlation time (IRCT) τR, often expressed as the rotational perturbation factor (RPF), ξR = τR/τRbulk
In simulation studies of water rotation in the protein hydration shell, the results obtained and the conclusions drawn depend critically on how the rotational correlation time is derived from the time correlation function (TCF)

Summary

Introduction

The dynamics of the protein-water interface is of fundamental importance for many biological processes. Once the MHz frequency dependence had been causally linked to buried water molecules, it became clear that 17O MRD provides, in addition to information about the buried water molecules, a model-independent global measure of water dynamics in the external hydration shell: the shell-averaged integral rotational correlation time (IRCT) τR, often expressed as the rotational perturbation factor (RPF), ξR = τR/τRbulk. During the past three decades, experimental studies of protein hydration dynamics have been supplemented by molecular dynamics (MD) simulations.. While the early simulations were often hampered by methodological issues, the present state-of-the-art, with more accurate modeling of interactions and greatly improved statistical sampling, can reliably deliver important insights about protein hydration dynamics. MD simulations have achieved at least semi-quantitative agreement with the RPF measured by 17O MRD, boosting confidence in the ability of simulations to unravel details well beyond experimental reach

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