Interactive molecular dynamics in virtual reality

: applications for protein-ligand systems

Abstract

The advent of Molecular Dynamics (MD) has provided the scientific community with the ability to impart atomic motion to previously static structures. This has been especially useful for proteins, where dynamics and structure determine
their biological function. Of course, proteins are inherently 3-Dimensional (3D) entities, often assembling themselves into complex and involved constructs. Virtual Reality (VR) provides an opportunity for its users to occupy a simulated space, visualising and interacting with intangible objects as if they were physical matter. Recently, the pioneering method of Interactive Molecular Dynamics in Virtual Reality (IMD-VR) allows scientists to visualise and interact with physically rigorous MD simulations from within a VR environment. This thesis is primarily concerned with the applications of IMD-VR, particularly using the software Narupa IMD developed at the University of Bristol. The use of IMD-VR for recreating crystallographic bound poses of three viral protein- ligand systems is explored, where both novice and expert IMD-VR users completed these docking challenges. The focus then shifts onto a pharmalogically relevant target, the SARS-CoV-2 Main Protease (Mpro), where IMD-VR best practices are established for docking a long, flexible oligopeptide and a small drug-like molecule. IMD-VR is then utilised as a predictive tool, generating bound structures of potential Mpro inhibitors. These are compared to structures generated from the automated docking software AutoDock CrankPep. Finally, drug unbinding pathways found via brute force MD and IMD-VR are compared structurally, and the use of IMD-VR as a method for creating intuitive, human-designed collective variables for enhanced MD methods to follow is proposed. Overall, IMD-VR is proposed as being a useful tool to add to the armoury of computational methods for studying biomolecules, particularly those of pharmacological significance.

Date of Award	21 Jun 2022
Original language	English
Awarding Institution	University of Bristol
Supervisor	Adrian J Mulholland (Supervisor) & David R Glowacki (Supervisor)