Water-glycan interactions drive the SARS-CoV-2 spike dynamics: insights into glycan-gate control and camouflage mechanisms.

To develop therapeutic strategies against COVID-19, we introduce a high-resolution all-atom polarizable model capturing many-body effects of protein, glycan, solvent, and membrane components in SARS-CoV-2 spike protein open and closed states. Employing μs-long molecular dynamics simulations powered by high-performance cloud-computing and unsupervised density-driven adaptive sampling, we investigated the differences in bulk-solvent-glycan and protein-solvent-glycan interfaces between these states. We unraveled a sophisticated solvent-glycan polarization interaction network involving the N165/N343 glycan-gate patterns that provide structural support for the open state and identified key water molecules that could potentially be targeted to destabilize this configuration.