ABSTRACT

In this communication we introduce an efficient implementation of adaptive biasing that greatly improves the speed of free energy computation in molecular dynamics simulations. We investigated the use of accelerated simulations to inform on compound design using a recently reported and clinically relevant inhibitor of the chromatin regulator BRD4 (bromodomain-containing protein 4). Benchmarking on our local compute cluster, our implementation achieves up to 2.5 times more force calls per day than plumed2. Results of five 1 μs-long simulations are presented, which reveal a conformational switch in the BRD4 inhibitor between a binding competent and incompetent state. Stabilization of the switch led to a −3 kcal/mol improvement of absolute binding free energy. These studies suggest an unexplored ligand design principle and offer new actionable hypotheses for medicinal chemistry efforts against this druggable epigenetic target class.