Antibody accessibility determines location of spike surface mutations in SARS-CoV-2 variants.

The steady emergence of SARS-CoV-2 variants gives us a real-time view of the interplay between viral evolution and the host immune defense. The spike protein of SARS-CoV-2 is the primary target of antibodies. Here, we show that steric accessibility to antibodies provides a strong predictor of mutation activity in the spike protein of SARS-CoV-2 variants, including Omicron. We introduce an antibody accessibility score (AAS) that accounts for the steric shielding effect of glycans at the surface of spike. We find that high values of the AAS correlate strongly with the sites of mutations in the spike proteins of newly emerging SARS-CoV-2 variants. We use the AAS to assess the escapability of variant spike proteins, i.e., their ability to escape antibody-based immune responses. The high calculated escapability of the Omicron variant BA.5 with respect to both wild-type (WT) vaccination and BA.1 infection is consistent with its rapid spread despite high rates of vaccination and prior infection with earlier variants. We calculated the AAS from structural and molecular dynamics simulation data that were available early in the pandemic, in the spring of 2020. The AAS thus allows us to prospectively assess the ability of variant spike proteins to escape antibody-based immune responses and to pinpoint regions of expected mutation activity in future variants.

Computational epitope map of SARS-CoV-2 spike protein.

The primary immunological target of COVID-19 vaccines is the SARS-CoV-2 spike (S) protein. S is exposed on the viral surface and mediates viral entry into the host cell. To identify possible antibody binding sites, we performed multi-microsecond molecular dynamics simulations of a 4.1 million atom system containing a patch of viral membrane with four full-length, fully glycosylated and palmitoylated S proteins. By mapping steric accessibility, structural rigidity, sequence conservation, and generic antibody binding signatures, we recover known epitopes on S and reveal promising epitope candidates for structure-based vaccine design. We find that the extensive and inherently flexible glycan coat shields a surface area larger than expected from static structures, highlighting the importance of structural dynamics. The protective glycan shield and the high flexibility of its hinges give the stalk overall low epitope scores. Our computational epitope-mapping procedure is general and should thus prove useful for other viral envelope proteins whose structures have been characterized.

In situ structural analysis of SARS-CoV-2 spike reveals flexibility mediated by three hinges.

The spike protein (S) of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is required for cell entry and is the primary focus for vaccine development. In this study, we combined cryo-electron tomography, subtomogram averaging, and molecular dynamics simulations to structurally analyze S in situ. Compared with the recombinant S, the viral S was more heavily glycosylated and occurred mostly in the closed prefusion conformation. We show that the stalk domain of S contains three hinges, giving the head unexpected orientational freedom. We propose that the hinges allow S to scan the host cell surface, shielded from antibodies by an extensive glycan coat. The structure of native S contributes to our understanding of SARS-CoV-2 infection and potentially to the development of safe vaccines.