LAUSR

Ongoing COVID-19 pandemic caused by new coronavirus, SARS-CoV-2, calls for urgent developments of vaccines and antiviral drugs. The spike protein of SARS-CoV-2 (S-protein), which consists of trimeric polypeptide chains with glycosylated residues on the surface, triggers the virus entry into a host cell. Extensive structural and functional studies on this protein have rapidly advanced our understanding of the S-protein structure at atomic resolutions, while most of structural studies overlook the effect of glycans attached to S-protein on the conformational stability and functional motions between the inactive Down and the active Up forms. Here, we performed all-atom molecular dynamics (MD) simulations of both Down and Up forms of a fully glycosylated S-protein in solution as well as targeted MD (TMD) simulations between them to elucidate key inter-domain interactions for stabilizing each form and inducing the large-scale conformational transitions. The residue-level interaction analysis of the simulation trajectories detects distinct amino-acid residues and N-glycans as determinants on conformational stability of each form. During the conformational transitions between them, inter-domain interactions mediated by glycosylated residues are switched to play key roles on the stabilization of another form. Electrostatic interactions as well as hydrogen bonds between the three receptor binding domains work as driving forces to initiate the conformational transitions toward the active form. This study sheds light on the mechanisms underlying conformational stability and functional motions of S-protein, which are relevant for vaccines and antiviral drugs developments.