Energy Decomposition Analysis of Protein-Ligand Interactions Using Molecules-in-Molecules Fragmentation-Based Method

Accurate prediction of protein–ligand binding affinities and their quantitative decomposition into residue-specific contributions represent challenging problems in drug discovery. While quantum mechanical (QM) methods can provide an accurate description of such interactions, the associated computational cost is normally prohibitive for broad-based applications. Recently, we have shown that QM-based protein–ligand interaction energies in the gas phase can be determined accurately using our multilayer molecules-in-molecules (MIM) fragmentation-based method at a significantly lower computational cost. In this paper, we present a new approach for calculating protein–ligand interactions using our three-layer model (MIM3) that allows us to decompose the total binding affinity into quantitative contributions from individual residues (or backbone and side chain), crystal water molecules, solvation energy, and entropy. In our approach, the desolvation energy and entropy changes during protein–ligand binding are mo...