Syma Khalid and Jon Essex (both from the University of Southampton)

The UK biomolecular simulation community has come together to characterise a number of the key proteins within the virus in an effort identify targets for vaccines and antivirals. We will provide a brief overview of these activities before focusing on studying the binding site of the SARS-CoV-2 main protease.

The Coronavirus Disease of 2019 (COVID-19) is caused by a novel coronavirus known as the Severe Acute Respiratory Syndrome coronavirus 2 (SARS-CoV-2). Despite extensive research since the outset of the pandemic it continues to spread with a high mortality rate. The main protease (MPro) of SARS-CoV-2 is an enzyme essential for virus replication through viral proteolytic activity and subsequent generation of infectious virus particles. Current computational efforts towards SARS-CoV-2MPro inhibitor design have often failed to consider the disruption of the His41-Cys145 catalytic dyad as a possible mechanism, and thus missed the opportunity to target the open conformational state. In this presentation, we use molecular dynamics and metadynamics simulations to sample this conformational change. We calculate a 1 +/- 0:45 kcal/mol free energy difference between the open and closed states of the SARS-CoV-2MPro active site. This indicates that favourable interactions with His41 over the Cys145-His41 dyad interaction can stabilise the open state, and that this state should be considered as part of inhibitor design efforts.

This online session is open to all. It will use the Blackboard Collaborate platform.