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

Interactive Molecular Dynamics in Virtual Reality (iMD-VR) Is an Effective Tool for Flexible Substrate and Inhibitor Docking to the SARS-CoV-2 Main Protease

“…In this work, we have demonstrated that iMD-VR is an effective tool for generating structures of complexes of the SARS-CoV-2 Mpro with an inhibitor-and an oligopeptide substrate. In previous work [31] we have shown that even novice users can quickly generate structures in good agreement with crystal structures, with minimal guidance. With a little practice, researchers can dock ligands to proteins in a few minutes.…”

“…traditional screen/mousebased methods. [29] We believe that such technologies will find widespread application in structure-based drug design [31], in other molecular modelling, design and simulation applications, and in education. [33] IMD-VR should be directly useful in ongoing efforts to develop Mpro inhibitors as potential antivirals against COVID-19, especially as others look to crowd-source the problem.…”

“…[43] Narupa, the software framework that we have developed, is open source, and uses commodity VR hardware, which is widely accessible. [29,31,33,44] It can therefore readily be used. We make our Mpro simulations here freely available; these can be used for ligand discovery and structure-activity studies for SARS-CoV-2.…”

Entering the Augmented Era: Immersive and Interactive Virtual Reality for Battery Education and Research**

“…In the recent years, VR technology started to be significantly used for educational and research purposes in hard sciences such as mathematics, physics and chemistry [21–25] . In chemistry, especially, researchers have proposed VR tools to visualize quantum mechanics and molecular dynamics simulation results or to teach experiments in immersive and interactive way [26–32] …”

Interactive Molecular Dynamics in Virtual Reality (iMD-VR) Is an Effective Tool for Flexible Substrate and Inhibitor Docking to the SARS-CoV-2 Main Protease

“…iMD-VR simulations were run similarly to the process described in previous work [5], including the use of trace atoms to act as a visual guide to the user. Trace atoms for the small ligand and substrate were extracted directly from PDB file 6W63 and 2Q6G, respectively.…”