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 .
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 .
R
Using molecular dynamics (MD) to simulate drug binding
Simulating drug binding and
R
. Because it requires sampling
, as the
R
, it has a high cost and
require extensive sampling that
R
a
an accurate
R
generating reversible
flexible
R
binding and unbinding pathways
docking
R
generate reversible pathways for guiding
guide
R
Detailed test carried out to evaluate the use of iMD-VR by novices showed that (following
Following
R
) they were similarly
, our studies shown that iMD-VR novices were
D
which recovered binding poses
R
the experts
iMD-VR experts, with the majority able to recover binding poses within 2.15 Angstrom RMSD of the crystallographic binding pose
R
generate reversible binding pathways that
carry out the detailed atomic manipulations required to dock flexible ligands into dynamic enzyme active sites and
R
a
an interesting
R
hypothesis
hypotheses