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

• Published in: Journal of chemical information and modeling 2017-07, Vol.57 (7), p.1652-1666
• Main Authors: Güssregen, Stefan, Matter, Hans, Hessler, Gerhard, Lionta, Evanthia, Heil, Jochen, Kast, Stefan M
• Format: Article
• Language: English
• Subjects: Binding Sites; Bioactive; Blood Proteins - chemistry; Blood Proteins - pharmacology; Chlorobenzoates - chemistry; Chlorobenzoates - pharmacology; Coordination compounds; Energy; Energy consumption; Factor VIIa - chemistry; Factor VIIa - metabolism; Factor Xa - chemistry; Factor Xa - metabolism; Factor Xa Inhibitors - chemistry; Factor Xa Inhibitors - pharmacology; Flux density; Free energy; Hydration; Integral equations; Ligands; Maxima; Molecular dynamics; Molecular Dynamics Simulation; Molecular structure; Molecules; Protease inhibitors; Protein Binding; Protein Conformation; Proteins; Proteins - antagonists & inhibitors; Proteins - chemistry; Proteins - metabolism; Quantitative Structure-Activity Relationship; Regression analysis; Solvation; Streptavidin - chemistry; Streptavidin - metabolism; Thermodynamics; Three dimensional models; Water; Water - metabolism; Water chemistry
• ISSN: 1549-9596; 1549-960X
• DOI: 10.1021/acs.jcim.6b00765

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.