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The hydration shells of proteins mediate interactions, such as small molecule binding, that are vital to their biological function or in some cases their dysfunction. However, even when the structure of a protein is known, the properties of its hydration environment cannot be easily predicted due to the complex interplay between protein surface heterogeneity and the collective structure of water’s hydrogen bonding network. This manuscript presents a theoretical study of the influence of surface charge heterogeneity on the polarization response of the liquid water interface. We focus our attention on classical point charge models of water, where the polarization response is limited to molecular reorientation. We introduce a new computational method for analyzing simulation data that is capable of quantifying water’s collective polarization response and determining the effective surface charge distribution of hydrated surfaces over atomistic length scales. To illustrate the utility of this method, we present the results of molecular dynamics simulations of liquid water in contact with a heterogeneous model surface and the CheY protein. 

The local hydration around tetrameric hemoglobin (Hb) in its T0 and R4 conformational substates is analyzed based on molecular dynamics simulations. Analysis of the local hydrophobicity (LH) for all residues at the α1β2 and α2β1 interfaces, responsible for the quaternary T → R transition, which is encoded in the Monod–Wyman–Changeux model, as well as comparison with earlier computations of the solvent accessible surface area, makes clear that the two quantities measure different aspects of hydration. Local hydrophobicity quantifies the presence and structure of water molecules at the interface, whereas “buried surface” reports on the available space for solvent. For simulations with Hb frozen in its T0 and R4 states, the correlation coefficient between LH and buried surface is 0.36 and 0.44, respectively, but it increases considerably if the 95% confidence interval is used. The LH with Hb frozen and flexible changes little for most residues at the interfaces but is significantly altered for a few select ones: Thr41α, Tyr42α, Tyr140α, Trp37β, Glu101β (for T0) and Thr38α, Tyr42α, Tyr140α (for R4). The number of water molecules at the interface is found to increase by ∼25% for T0 → R4, which is consistent with earlier measurements. Since hydration is found to be essential to protein function, it is clear that hydration also plays an essential role in allostery. 

Abstract The influenza B M2 protein forms a water-filled tetrameric channel to conduct protons across the lipid membrane. To understand how channel water mediates proton transport, we have investigated the water orientation and dynamics using solid-state NMR spectroscopy and molecular dynamics (MD) simulations. 13 C-detected water 1 H NMR relaxation times indicate that water has faster rotational motion in the low-pH open channel than in the high-pH closed channel. Despite this faster dynamics, the open-channel water shows higher orientational order, as manifested by larger motionally-averaged 1 H chemical shift anisotropies. MD simulations indicate that this order is induced by the cationic proton-selective histidine at low pH. Furthermore, the water network has fewer hydrogen-bonding bottlenecks in the open state than in the closed state. Thus, faster dynamics and higher orientational order of water molecules in the open channel establish the water network structure that is necessary for proton hopping.