Thermodynamic analysis of water molecules at the surface of proteins and applications to binding site prediction and characterization

Abstract

Water plays an essential role in determining the structure and function of all biological systems. Recent methodological advances allow for an accurate and efficient estimation of the thermodynamic properties of water molecules at the surface of proteins. In this work, we characterize these thermodynamic properties and relate them to various structural and functional characteristics of the protein. We find that high-energy hydration sites often exist near protein motifs typically characterized as hydrophilic, such as backbone amide groups. We also find that waters around alpha helices and beta sheets tend to be less stable than waters around loops. Furthermore, we find no significant correlation between the hydration site-free energy and the solvent accessible surface area of the site. In addition, we find that the distribution of high-energy hydration sites on the protein surface can be used to identify the location of binding sites and that binding sites of druggable targets tend to have a greater density of thermodynamically unstable hydration sites. Using this information, we characterize the FKBP12 protein and show good agreement between fragment screening hit rates from NMR spectroscopy and hydration site energetics. Finally, we show that water molecules observed in crystal structures are less stable on average than bulk water as a consequence of the high degree of spatial localization, thereby resulting in a significant loss in entropy. These findings should help to better understand the characteristics of waters at the surface of proteins and are expected to lead to insights that can guide structure-based drug design efforts.

A Single Glycine in Extracellular Loop 1 Is the Critical Determinant for Pharmacological Specificity of Dopamine D2 and D3 Receptors

“…The displacement of hydration sites with high free energy contributes favorably to the affinity of a ligand. Recent benchmark studies have documented the ability of this method to distinguish binding sites of low and high affinities (Beuming et al, 2012;Mason et al, 2012). When the D3R-Ptm23 subpocket is occupied by R-22, a cluster of three high-energy hydration sites is displaced by the indole ring, consistent with the high affinity of Ptm23-bound R-22 in D3R (Fig.…”

Probing water micro-solvation in proteins by water catalysed proton-transfer tautomerism

“…Recent advances have provided more convincing evidence that the water molecules in proteins are key elements in activating bio-functionality such as enzymatic reactions [4][5][6][7] or vice versa, the protein (for example, an antifreeze protein) may affect the organization of water molecules 8 . Probing the water environment of a specifically interesting site in proteins thus may pave a way to understanding the underlying mechanisms and functionality.…”

Role of Water in Ligand Binding to Maltose-Binding Protein: Insight from a New Docking Protocol Based on the 3D-RISM-KH Molecular Theory of Solvation

“…22,24,36 This can be done, for example, by ranking water molecules binding affinities obtained with the free-energy perturbation calculations 36 or by using the thermodynamic analysis with different solvation models based on explicit solvent MD simulations. 72 While such free energy calculations can provide useful information on binding affinities of water molecules in and around a binding site, in many practical applications more computationally efficient and fast approaches are needed. In this study, we use a protocol based on the hydrophobicity scale 65 of residues in proximity of a putative binding site.…”