Biomolecular Recognition Based on 3D Molecular Theory of Solvation

Abstract

Protein-protein and protein-ligand recognition plays an essential role in many biomolecular processes. Understanding the mechanisms of protein-ligand binding is also crucial for designing new and optimizing existing therapeutic agents, and in different biotechnological applications. It is well known that solvation effects, including hydrophobicity and solvent mediated hydrogen bonding, are major factors implicated in biomolecular processes. Such processes often involve slow conformational changes and exchange of solvent and ligand molecules between bulk solution and biomolecular cavities.We develop new approaches for accurate account of molecular solvation effects in protein-ligand recognition and binding, which further extend the ligand mapping protocols based on the molecular theory of solvation, a.k.a. the three-dimensional reference interaction site model with the Kovalenko-Hirata closure (3D-RISM-KH). Based on statistical mechanics, this theory provides a natural link between different levels of coarse-graining details in a multiscale description of solvation structure and thermodynamics, from highly localized structural solvent and bound ligand molecules to effective desolvation potentials and self-assembling nanoarchitectures in solvents of different composition in a range of thermodynamic conditions.Implemented in the new 3D-RISM-Dock protocol, the theory provides a quantitative estimate of binding affinities, based on a detailed physical description of hydrogen bonding, hydrophobicity, and solvation entropic effects, with full account for molecular specificities, thermodynamic conditions, and concentration effects. The theory accurately predicts the solvation structure of biomolecules. This allows us to incorporate the 3D-RISM-KH description of structural solvation in a new docking protocol. The latter has been successfully applied to predict the binding modes of the periplasmic binding proteins in situations when structural solvation and desolvation effects are of importance. We also show that the 3D-RISM-KH theory provides valuable information on the role of the solvation entropic effects in the ligand binding and large scale conformation dynamics of proteins.