Thermodynamic Characterization of Hydration Sites from Integral Equation-Derived Free Energy Densities: Application to Protein Binding Sites and Ligand Series

Abstract

Water molecules play an essential role for mediating interactions between ligands and protein binding sites. Displacement of specific water molecules can favorably modulate the free energy of binding of protein-ligand complexes. Here, the nature of water interactions in protein binding sites is investigated by 3D RISM (three-dimensional reference interaction site model) integral equation theory to understand and exploit local thermodynamic features of water molecules by ranking their possible displacement in structure-based design. Unlike molecular dynamics-based approaches, 3D RISM theory allows for fast and noise-free calculations using the same detailed level of solute-solvent interaction description. Here we correlate molecular water entities instead of mere site density maxima with local contributions to the solvation free energy using novel algorithms. Distinct water molecules and hydration sites are investigated in multiple protein-ligand X-ray structures, namely streptavidin, factor Xa, and factor VIIa, based on 3D RISM-derived free energy density fields. Our approach allows the semiquantitative assessment of whether a given structural water molecule can potentially be targeted for replacement in structure-based design. Finally, PLS-based regression models from free energy density fields used within a 3D-QSAR approach (CARMa - comparative analysis of 3D RISM Maps) are shown to be able to extract relevant information for the interpretation of structure-activity relationship (SAR) trends, as demonstrated for a series of serine protease inhibitors.

Lipophilicity in Drug Design: An Overview of Lipophilicity Descriptors in 3D-QSAR Studies

“…By using a classical statistical mechanics-based solvent model combined with machine learning, 1D solute-solvent correlation functions were used to predict Caco-2 cell permeabilities [70]. As an extension of this approach, Güssregen et al proposed the Comparative Analysis of 3D-RISM Maps (CARMa) methodology [71]. In this computational strategy, the classical electrostatic and steric fields generally used in CoMFA are replaced by solute-solvent distribution functions determined from 3D-RISM computations, which are subsequently treated as descriptors to perform QSAR analysis.…”

Comparative Molecular Field Analysis Using Molecular Integral Equation Theory

“…It is also the same number of latent variables that was used in the original studies on CoMFA and CARMa methods. 7,21 Random Forest…”

“…20 Recently, Güssregen et al proposed the Comparative Analysis of 3D RISM Maps (CARMa) methodology, which uses solute-solvent distribution functions calculated by 3DRISM to replace the electrostatic or steric fields in CoMFA. 21 This approach was shown to give accurate predictions of binding affinities for a series of serine protease inhibitors, but tests on other systems have not yet been published. 21 The purpose of this article is two-fold.…”

“…21 This approach was shown to give accurate predictions of binding affinities for a series of serine protease inhibitors, but tests on other systems have not yet been published. 21 The purpose of this article is two-fold. Firstly, we propose an extension to the CARMa methodology.…”

A molecular reconstruction approach to site-based 3D-RISM and comparison to GIST hydration thermodynamic maps in an enzyme active site

“…This causes problems when attempting to estimate the free energy of a ligand displacing water from a binding site into bulk; a slight shift in the position of a ligand may produce very different predictions of the energetic cost of displacing the solvent. This problem has been addressed by either averaging the contributions of solvent over coarser grids[30] or collapsing them on to solvation sites[31], but both approaches sacrifice the detailed information contained in the density distributions.…”