Sampling protein-ligand binding pathways to recover crystallographic binding poses using interactive molecular dynamics in virtual reality

Using molecular dynamics (MD) to simulate drug binding & unbinding is a challenge. Because it requires sampling rugged energy landscapes that separate bound and unbound states, it has a high cost and consumes significant computational resources. Here, we describe the use of interactive molecular dynamics in virtual reality (iMD-VR) as a low-cost strategy for generating reversible protein-ligand binding and unbinding pathways. We outline an experimental protocol which enables expert iMD-VR users to generate reversible pathways for guiding ligands into and out of the binding pockets of trypsin, neuraminidase, and HIV-1 protease, and recreate their respective crystallographic protein-ligand binding poses within 5 - 10 minutes. Detailed test carried out to evaluate the use of iMD-VR by novices showed that (following a brief training phase) they were similarly able to generate unbinding and rebinding pathways which recovered binding poses on similar timescales as the experts. These results indicate that iMD-VR affords sufficient control for users to generate reversible binding pathways that recover crystallographic poses, offering a new approach for simulating drug docking and generating binding hypothesis.