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Protein Hydration Waters are Susceptible to Unfavorable Perturbations Nicholas B Rego, Erte Xi, and Amish Jagdish Patel J. Am. Chem. Soc., Just Accepted Manuscript • Publication Date (Web): 07 Jan 2019 Downloaded from http://pubs.acs.org on January 7, 2019
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Journal of the American Chemical Society
Protein Hydration Waters are Susceptible to Unfavorable Perturbations Nicholas B. Rego,† Erte Xi,‡ and Amish J. Patel∗,‡ †Biochemistry & Molecular Biophysics Graduate Group, University of Pennsylvania, Philadelphia, PA 19104 ‡Department of Chemical & Biomolecular Engineering, University of Pennsylvania, Philadelphia, PA 19104 E-mail:
[email protected] Abstract
and phase behavior of protein solutions. 11–18 In this article, we characterize the overall interactions between proteins and their hydration waters by using specialized molecular simulations that employ an unfavorable potential to displace water molecules from the vicinity of a protein. Because displacing interfacial waters disrupts surface-water interactions, the less favorable those interactions (e.g., for hydrophobic surfaces), the easier it is to displace the interfacial waters. 19–21 Indeed, both theory 22–25 and molecular simulations 26,27 have shown that the rare, lowdensity fluctuations, which are accessed when interfacial waters are displaced, are substantially more probable adjacent to a hydrophobic surface (than at a hydrophilic surface). Such enhanced low-density fluctuations situate water near extended hydrophobic surfaces at the edge of a collective dewetting transition, making them susceptible to unfavorable potentials. 22,26,27 The proximity of interfacial waters to a dewetting transition is also reflected in other collective interfacial properties, such as compressibility, transverse density correlations, and the distribution of water dipole orientations, among others. 19,22,26–35 In contrast with simple hydrophobic or hydrophilic surfaces, proteins display nanoscopic chemical and topographical patterns, which influence their interactions with water in nontrivial ways. 20,36–48 By interrogating how pro-
The interactions of a protein, its phase behavior, and ultimately, its ability to function, are all influenced by the interactions between the protein and its hydration waters. Here we study proteins with a variety of sizes, shapes, chemistries, and biological functions, and characterize their interactions with their hydration waters using molecular simulations and enhanced sampling techniques. We find that akin to extended hydrophobic surfaces, proteins situate their hydration waters at the edge of a dewetting transition, making them susceptible to unfavorable perturbations. We also find that the strength of the unfavorable potential needed to trigger dewetting is roughly the same for all the proteins studied here, and depends primarily on the width of the hydration shell being perturbed. Our findings establish a framework for systematically classifying protein patches according to how favorably they interact with water.
Introduction Biomolecular binding processes involve disrupting protein-water interactions and replacing them with direct interactions between the binding partners. Thus, protein-water interactions influence the thermodynamics and kinetics of protein interactions, 1–10 as well as the stability
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tein hydration waters respond to an unfavorable potential, here we find that the hydration shells of diverse proteins are also situated at the edge of a dewetting transition. Such a resemblance of protein hydration shells to extended hydrophobic surfaces appears to arise from the fact that – even for protein surfaces that are enriched in polar and charged residues – roughly half the surface consists of hydrophobic atoms. Our findings, obtained by studying proteins across a broad range of sizes, chemistries, and functions, suggest that susceptibility to unfavorable perturbations is a common feature of soluble proteins with well-defined folded structures. We also find that the strength of the unfavorable potential needed to trigger dewetting is inversely proportional to the width of the hydration shell that we choose to perturb, but is otherwise similar across all the proteins that we study. Our findings lay the groundwork for systematically disrupting protein-water interactions, and uncovering regions of proteins that have the weakest (hydrophobic) and the strongest (hydrophilic) interactions with water. A knowledge of the most hydrophobic protein regions could enable the prediction of the interfaces through which protein interact with one another. 49–52 Similarly, uncovering the most hydrophilic protein patches could result in the discovery of novel super-hydrophilic chemical patterns. 53
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SAM-water interface, as shown in Figure 1a. We choose a radius, Rv = 2 nm, and a width, w = 0.3 nm, for the cylindrical v; with this choice, v at either SAM surface contains an average of roughly 120 waters. Following previous work, 27 we then perturb the interfacial waters in v by applying an unfavorable biasing potential, φNv , where φ represents the strength of the potential, and Nv is the number of coarsegrained waters in v; a more precise definition of Nv is included in the Supporting Information. 56 The potential imposes an energetic penalty that increases linearly with Nv , so that as φ is increased, waters are displaced from v, resulting in a decrease in the average water numbers, hNv iφ , next to both SAM surfaces; see Figure 1b. The decrease in hNv iφ with increasing φ is linear for the hydrophilic SAM. In comparison, the corresponding hNv iφ -values for the hydrophobic SAM are smaller for every φ, highlighting the relative ease of displacing waters. Moreover, the decrease in hNv iφ with increasing φ is sensitive (or sigmoidal) near the hydrophobic surface rather than gradual (and linear) as it is near the hydrophilic surface. This contrast can be seen even more clearly in Figure 1c, which shows the susceptibility, χv ≡ −∂hNv iφ /∂(βφ), as a function of βφ; here, β = 1/kB T , kB is the Boltzmann constant, and T is the system temperature. The susceptibility is nearly constant for the hydrophilic surface. However, it shows a pronounced peak for the hydrophobic surface, suggesting that a collective dewetting of the interfacial waters can be triggered when a sufficiently strong unfavorable potential is applied. 27
Results and Discussion Water near uniform, flat surfaces To illustrate the molecular signatures of surface hydrophobicity, we first review the contrasting behavior of water near CH3 -terminated (hydrophobic) and OH-terminated (hydrophilic) self-assembled monolayer (SAM) surfaces, as was done in ref. 27 The SAM surfaces are not only flat and uniform, and thereby considerably simpler than proteins, but their hydrophobicity can also be defined unambiguously using a macroscopic measure, such as the water droplet contact angle. We focus on water molecules in a cylindrical observation volume, v, at the
Perturbing the protein hydration shell Unlike the uniform SAM surfaces, proteins are heterogeneous, rugged, and amphiphilic. In ref., 27 enhanced low-density fluctuations, which underpin susceptibility to dewetting, were observed adjacent to a hydrophobic patch on the BphC protein, whereas bulk-like (Gaussian) fluctuations were seen near a hydrophilic patch on the protein. However, in contrast with individual protein patches, protein surfaces on the
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