Energy Decomposition Analysis of Protein-Ligand Interactions Using Molecules-in-Molecules Fragmentation-Based Method
Abstract
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 multi-layer 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 modeled using simple and inexpensive empirical models while intermolecular interactions are computed using an accurate QM method. The performance of our approach has been assessed on a congeneric series of 22 thrombin inhibitors, all with experimentally known binding affinities, using a binding pocket cutout of 120 residues with more than 1550 atoms. Comparison of our MIM3-calculated binding affinities calculated at B97-D3BJ/6-311++G(2d,2p) level with experiment shows a good…
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