Structural dynamics in the evolution of SARS-CoV-2 spike glycoprotein

Abstract

SARS-CoV-2 spike glycoprotein mediates receptor binding and subsequent membrane fusion. It exists in a range of conformations, including a closed state unable to bind the ACE2 receptor, and an open state that does so but displays more exposed antigenic surface. Spikes of variants of concern (VOCs) acquired amino acid changes linked to increased virulence and immune evasion. Here, using HDX-MS, we identified changes in spike dynamics that we associate with the transition from closed to open conformation, to ACE2 binding, and to specific mutations in VOCs. We show that the RBD-associated subdomain plays a role in spike opening, whereas the NTD acts as a hotspot of conformational divergence of VOC spikes driving immune evasion. Alpha, beta and delta spikes assume predominantly open conformations and ACE2 binding increases the dynamics of their core helices, priming spikes for fusion. Conversely, substitutions in omicron spike lead to predominantly closed conformations, presumably enabling it to escape antibodies. At the same time, its core helices show characteristics of being pre-primed for fusion even in the absence of ACE2. These data inform on SARS-CoV-2 evolution and omicron emergence.

Ensemble-Based Modeling of the SARS-CoV-2 Omicron BA.1 and BA.2 Spike Trimers and Systematic Characterization of Cryptic Binding Pockets in Distinct Functional States : Emergence of Conformation-Sensitive and Variant-Specific Allosteric Binding Sites

“…Other latest studies highlighted conformational plasticity of the NTD regions where mutations/deletions not only change the architecture, but also alter the surface properties, leading to remodeling of the binding pockets and major antigenic changes in the NTD supersite and loss of antibody binding [63]. These studies support the recent data suggesting that the NTD of the S protein can serve as an adaptable antigenic surface capable of unlocking and redistributing cryptic binding pockets which may enable the virus to divert the host immune responses away from the RBD regions [50].Computer simulations provided important atomistic and mechanistic advances into understanding the dynamics and function of the SARS-CoV-2 S proteins. [64][65][66][67][68][69][70].…”

“…The observed patterns of collective motions in the S-BA.1 and S-BA.2 states are also consistent with the recent experiments showing the increasing flexibility of the NTD regions in the Omicron trimers which may enable escape of NTD-targeting antibodies thereby providing an evolutionary advantage. The observed in our dynamics analysis differences in modulation of the NTD mobility between BA.1 and BA.2 conformations supports the proposed mechanism in which NTD provides an adaptable antigenic surface, allowing for enhanced immune escape potential [50].…”

“…The hidden dynamic nature of the S trimers was elucidated using hydrogen-deuterium exchange monitored by mass spectrometry (HDX-MS) [49] uncovering an alternative open trimer conformation that interconverts slowly with the canonical prefusion structures and can dynamically expose novel epitopes in the conserved region of the S2 trimer interface, providing new epitopes in a highly conserved region of the protein. Another HDX-MS study we identified changes in the S dynamics for VOCs, revealing that Omicron mutations may preferentially induce closed conformations and that the NTD acts as a hotspot of conformational divergence driving immune evasion [50]. It was found that the divergence hotspot overlaps with the NTD antigenic supersite [51] and that the increased flexibility acquired by early VOC's and Omicron variants promotes immune escape of NTD-targeting antibodies [52].…”

“…The copyright holder for this preprint this version posted August 23, 2023. ; https://doi.org/10.1101/2023.08.…”

Water-Glycan Interactions Drive the SARS-CoV-2 Spike Dynamics: Insights into Glycan-Gate Control and Camouflage Mechanisms

“…Given the prevalence and role of α-D-mannose residues in viral attachment (6,21,(35)(36)(37), we also evaluated their contribution to the glycan radial motion. In the closed state, the radial distances of these residues closely matched the total glycan radial distances (Fig.…”