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

PloS One
Helen M DeeksDavid R Glowacki

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.

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Citations

Jul 26, 2021·European Journal of Medicinal Chemistry·Victor T SabeHendrik G Kruger
Nov 13, 2020·Journal of Chemical Information and Modeling·Jordi Juárez-JiménezJulien Michel
Aug 20, 2021·Biochemistry and Molecular Biology Education : a Bimonthly Publication of the International Union of Biochemistry and Molecular Biology·Jim CookPhilip Poronnik

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Methods Mentioned

BETA
PCA

Software Mentioned

iMD VR
Narupa
VR
PathReducer
iMD

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