A fast, open source implementation of adaptive biasing potentials uncovers a ligand design strategy for the chromatin regulator BRD4

摘要

In this communication we introduce an efficient implementation of adaptivebiasing that greatly improves the speed of free energy computation in moleculardynamics simulations. We investigated the use of accelerated simulations toinform on compound design using a recently reported and clinically relevantinhibitor of the chromatin regulator BRD4. Benchmarking on our local computecluster, our implementation achieves up to 2.5 times more force calls per daythan plumed2. Results of five 1{\mu}second-long simulations are presented,which reveal a conformational switch in the BRD4 inhibitor between a bindingcompetent and incompetent state. Stabilization of the switch led to a -3kcal/mol improvement of absolute binding free energy. These studies suggest anunexplored ligand design principle and offer new actionable hypotheses formedicinal chemistry efforts against this druggable epigenetic target class.