J Chem Theory Comput 17 (4) 2479-2487 [2021-04-13; online 2021-03-10]
The spike (S) protein of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) mediates host cell entry by binding to angiotensin-converting enzyme 2 (ACE2) and is considered the major target for drug and vaccine development. We previously built fully glycosylated full-length SARS-CoV-2 S protein models in a viral membrane including both open and closed conformations of the receptor-binding domain (RBD) and different templates for the stalk region. In this work, multiple μs-long all-atom molecular dynamics simulations were performed to provide deeper insights into the structure and dynamics of S protein and glycan functions. Our simulations reveal that the highly flexible stalk is composed of two independent joints and most probable S protein orientations are competent for ACE2 binding. We identify multiple glycans stabilizing the open and/or closed states of the RBD and demonstrate that the exposure of antibody epitopes can be captured by detailed antibody-glycan clash analysis instead of commonly used accessible surface area analysis that tends to overestimate the impact of glycan shielding and neglect possible detailed interactions between glycan and antibodies. Overall, our observations offer structural and dynamic insights into the SARS-CoV-2 S protein and potentialize for guiding the design of effective antiviral therapeutics.