Abstract
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.
Highlights
The outbreak of Coronavirus disease 2019 (COVID-19) caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) presents a tremendous threat to global public health
A number of recently published structural studies using cryogenic electron microscopy have provided a good understanding of the S protein structure at near-atomic resolution.[4,10−12] The S1 subunit responsible for receptor binding is composed of the signal peptide (SP), N terminal domain (NTD), and receptorbinding domain (RBD), and the S2 subunit responsible for membrane fusion is composed of the fusion peptide (FP), two heptad repeats (HR1 and HR2), transmembrane domain (TM), and cytoplasmic domain (CP)
While both model 1 (M1) and model 2 (M2) of the HR2 linker show similar twist angle distributions (φ) centered at 66° (±46°) and 68° (±49°), respectively, the M1 of HR2TM shows a narrow distribution centered at 99° (±18°) and the M2 of HR2-TM shows a wide distribution centered at 98° (±71°)
Summary
The outbreak of Coronavirus disease 2019 (COVID-19) caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) presents a tremendous threat to global public health. It caused over 35 million confirmed cases and more than 1 million deaths as of October, 2020. All three RBDs lay flat with the receptorbinding motif occluded by the RBDs on the neighboring monomers. One or multiple RBDs lift up and expose the receptor-binding motif(s)
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