(673j) A Coarse-Grained Perspective on Key Interfaces and Kinetic Mechanisms for Viral Self-Assembly

The self-assembly of structural proteins is central to the function of viruses, including human immunodeficiency virus type-1 (HIV-1) and severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), the latter of which is responsible for the COVID-19 pandemic. Understanding the fundamental molecular mechanisms that regulate viral protein assembly will advance basic biophysical science and provide insight into potential therapeutic strategies. To investigate viral assembly processes, our strategy is to systematically derive coarse-grained (CG) protein models combined with enhanced sampling techniques in order to access experimentally-relevant spatiotemporal scales that are inaccessible to conventional molecular dynamics (MD) simulations. Our CG simulations reveal the importance of multiple configurational modes that are encoded in structural HIV-1 and SARS-CoV-2 proteins. Under precise environmental conditions, which can result from the modulation of cellular cofactors, salt concentration, inert crowding agents, or membrane mechanical properties, we find that protein interfaces pertinent to association are exposed, although the population of these states remains rare. We show that varying these environmental conditions controls the resultant morphology of assembled proteins, which includes spherical virus-like particles or cylindrical tubules, on the basis of protein interaction strengths and configurational state kinetics. Our simulations suggest mechanisms by which viruses can simultaneous avoid kinetic traps (e.g. misaggregation) and evade immune responses. We conclude with potential directions for anti-retroviral therapies.