Capturing Water Networks during Ligand Binding with the Site-Identification by Ligand Competitive Saturation-Monte Carlo Approach

Abstract

Listen

Translate article

Water molecules impact interactions between proteins and their ligands, making a significant contribution to ligand binding orientation and affinity. Water molecules can significantly affect the energetics of ligand binding in a favorable or unfavorable manner associated, in part, with the energetic penalty for displacing waters that occupy a binding site. In computer-aided drug design, the challenge is to calculate water mediated interactions and their energetics between the ligand and the protein. In this work, an extension of the Site Identification by Ligand Competitive Saturation-Monte Carlo (SILCS-MC) docking approach is presented to determine the positioning of the water molecules in the binding site and estimate the energetic contribution of water to ligand binding. We employ this methodology on variety of protein targets where water mediated interactions between the protein and ligands plays an important role. The efficacy of this approach is reflected in rank-ordering ligand affinities, binding affinities predictions, and structure orientation of the ligands. The SILCS methodology is of utility for characterization of functional group affinities for the entire 3D region encompassed by a protein or other macromolecule. This approach is based on sampling the conformational space of multiple solutes representing various functional groups in the presence of explicit water of a protein target using a combination of oscillating chemical potential Grand Canonical Monte Carlo and Molecular Dynamics simulations. The presented approach offers new possibilities in revealing water networks and their contributions to the binding affinity of a ligand to a protein.