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

The
main protease (Mpro) of the SARS-CoV-2 virus is one focus of
drug development efforts for COVID-19. Here, we show that interactive
molecular dynamics in virtual reality (iMD-VR) is a useful and effective
tool for creating Mpro complexes. We make these tools and models freely
available. iMD-VR provides an immersive environment in which users
can interact with MD simulations and so build protein complexes in
a physically rigorous and flexible way. Recently, we have demonstrated
that iMD-VR is an effective method for interactive, flexible docking
of small molecule drugs into their protein targets (Deeks et al. PLoS One 2020, 15, e0228461). Here, we apply this approach to both an Mpro inhibitor and an
oligopeptide substrate, using experimentally determined crystal structures.
For the oligopeptide, we test against a crystallographic structure
of the original SARS Mpro. Docking with iMD-VR gives models in agreement
with experimentally observed (crystal) structures. The docked structures
are also tested in MD simulations and found to be stable. Different
protocols for iMD-VR docking are explored, e.g., with and without
restraints on protein backbone, and we provide recommendations for
its use. We find that it is important for the user to focus on forming
binding interactions, such as hydrogen bonds, and not to rely on using
simple metrics (such as RMSD), in order to create realistic, stable
complexes. We also test the use of apo (uncomplexed) crystal structures
for docking and find that they can give good results. This is because
of the flexibility and dynamic response allowed by the physically
rigorous, atomically detailed simulation approach of iMD-VR. We make
our models (and interactive simulations) freely available. The software
framework that we use, Narupa, is open source, and uses commodity
VR hardware, so these tools are readily accessible to the wider research
community working on Mpro (and other COVID-19 targets). These should
be widely useful in drug development, in education applications, e.g.,
on viral enzyme structure and function, and in scientific communication
more generally.