Interactive molecular dynamics in virtual reality for accurate flexible protein-ligand docking

TL;DR

This paper demonstrates that interactive molecular dynamics in virtual reality (iMD-VR) is an effective, low-cost method for flexible protein-ligand docking, enabling users to accurately recreate binding poses within minutes.

Contribution

The study introduces an experimental protocol for using iMD-VR in flexible protein-ligand docking, showing it can produce accurate binding poses rapidly and with minimal training.

Findings

Novices can generate unbinding and rebinding pathways quickly.

Users can recover crystallographic binding poses within 2.15 Å RMSD.

iMD-VR is effective for detailed atomic manipulations in drug docking.

Abstract

Simulating drug binding and unbinding is a challenge, as the rugged energy landscapes that separate bound and unbound states require extensive sampling that consumes significant computational resources. Here, we describe the use of interactive molecular dynamics in virtual reality (iMD-VR) as an accurate low-cost strategy for flexible protein-ligand docking. We outline an experimental protocol which enables expert iMD-VR users to guide 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. Following a brief training phase, our studies shown that iMD-VR novices were able to generate unbinding and rebinding pathways on similar timescales as iMD-VR experts, with the majority able to recover binding poses within 2.15 Angstrom RMSD of the crystallographic binding pose. These results indicate that iMD-VR affords sufficient control for users to carry out the detailed atomic manipulations required to dock flexible ligands into dynamic enzyme active sites and recover crystallographic poses, offering an interesting new approach for simulating drug docking and generating binding hypotheses.