BRD4: quantum mechanical protein-ligand binding free energies using the full-protein DFT-based QM-PBSA method.

Abstract

Fully quantum mechanical approaches to calculating protein-ligand free energies of binding have the potential to reduce empiricism and explicitly account for all physical interactions responsible for protein-ligand binding. In this study, we show a realistic test of the linear-scaling DFT-based QM-PBSA method to estimate quantum mechanical protein-ligand binding free energies for a set of ligands binding to the pharmaceutical drug-target bromodomain containing protein 4 (BRD4). We show that quantum mechanical QM-PBSA is a significant improvement over traditional MM-PBSA in terms of accuracy against experiment and ligand rank ordering and that the quantum and classical binding energies are converged to a similar degree. We test the interaction entropy and normal mode entropy correction terms to QM- and MM-PBSA.