Coarse-grained Modeling of SARS-CoV-2 Spike Protein Intermediates on the Pathway to Membrane Fusion

Entry of the SARS-CoV-2 virus into host cells is accomplished by the surface spike (S) glycoprotein, a class I fusion protein. Binding to target membrane ACE2 receptors is mediated by the S1 subunit. Following proteolytic processing, the S2 subunit then mediates fusion of the viral envelope and host cell membranes, resulting in a fusion pore that connects viral and host cell lumens for delivery of the viral genome. Fusion is achieved by several complex transitions taking the S2 subunit from the pre-fusion structure to the post-fusion structure, coupled to interactions with the host membrane. The pre- and post-fusion structures are partially characterized, but little is established about the intermediate states or the dynamical processes along this pathway, including fusion peptide release and its insertion into the host target membrane. A major challenge for computational approaches has been the long timescales characterizing these conformational changes and membrane interactions. As these timescales are beyond current all-atom approaches, coarse-grained (CG) molecular dynamics (MD) simulation approaches are needed. We will use CG and ultra coarse-grained (UCG) representations to study the structure and dynamics of these intermediates and their interactions with host membranes on realistically long timescales. In an integrated multiscale approach, finer grained simulations will calibrate more CG simulations to enable systematic CG parameter choices. This approach will allow assessment of antiviral strategies that target the pathway to membrane fusion, an important therapeutic target. Since the S2 fusion domain is conserved among coronaviruses, such antivirals offer the exciting possibility of pan-CoV therapeutics.