WaterKit: thermodynamic profiling of protein hydration sites

01 November 2022, Version 1
This content is a preprint and has not undergone peer review at the time of posting.

Abstract

Water desolvation is one of the key components of the free energy of binding of small molecules to their receptors. Thus, understanding the energetic balance of solvation and desolvation resulting from individual water molecules can be crucial when estimating ligand binding, especially when evaluating different molecules and poses as done in High-Throughput Virtual Screening (HTVS). Over the last decades, several methods were developed to tackle this problem, ranging from fast approximate methods (usually empirical functions using either discrete atom-atom pairwise interactions or continuum solvent models), to more computationally expensive and accurate ones mostly based on Molecular Dynamics (MD) simulations, such as Grid Inhomogeneous Solvation Theory (GIST) or Double Decoupling. On one hand, MD-based methods are prohibitive to use in HTVS to estimate the role of waters on the fly for each ligand. On the other hand, fast and approximate methods show unsatisfactory level of accuracy, with low agreement with results obtained with the more expensive methods. Here we introduce WaterKit, a new grid-based sampling method with explicit water molecules to calculate thermodynamic properties using the GIST method. Our results show that the discrete placement of water molecules is successful in reproducing the position of crystallographic waters with very high accuracy, as well as providing thermodynamic estimates with accuracy comparable to more expensive MD simulations. Unlike these methods, WaterKit can be used to analyze specific regions on the protein surface, (such as the binding site of a receptor), without having to hydrate and simulate the whole receptor structure. The results show the feasibility of a general and fast method to compute thermodynamic properties of water molecules, making it well suited to be integrated in high-throughput pipelines such as molecular docking.

Keywords

Autodock
docking
gist
free energy
thermodynamics
protein solvation

Supplementary materials

Title
Description
Actions
Title
Supplementary Material for WaterKit: thermodynamic profiling of protein hydration sites
Description
Force field parameters; extra tables and figures with comparison WK/MD for all systems; convergence analysis plots; GIST components analysis for all systems;
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Supplementary weblinks

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