A structural dynamic explanation for observed escape of SARS-CoV-2 BA.2 variant mutation S371L/F

Abstract

Upon emergence, the SARS-CoV-2 Omicron sub-variant BA, was identified to have increased transmissibility and immune evasion and has since become the dominant variant worldwide. Subsequently, the Omicron sub-variant BA.2 was observed to have a growth advantage as compared to BA.13. In response to the rise of BA.1 and BA.2, scientists worldwide have raced to computationally and experimentally characterize the decreased efficacy of current vaccines and therapeutic antibodies that were designed to target the wild-type Wuhan SARS-COV-2 strain. Specifically, two recent studies by Liu et al. and Iketani et al. provide a detailed analysis of loss of potency by evaluating vaccine/convalescent sera and therapeutic antibodies against pseudotyped viruses with D614G spike proteins harboring single point mutations from the variants of concern (VOCs). This characterization of individual variant mutations improves our mechanistic understanding of RBD antigenic space, facilitating next-generation antibody and vaccine design and interpretation of future variant phenotypes.

Using Haplotype-Based Artificial Intelligence to Evaluate SARS-CoV-2 Novel Variants and Mutations

“…These S371L/F mutations, commonly observed for BA.1 and BA.2, may have been associated with a perturbation of spike trimer conformational dynamics. 32 Additionally, 8 novel mutations (NSP1-K141/S142/F143, NS3-H78, and spike-L24/P25/I68/A684) appeared to be increasing in prevalence recently and may require careful monitoring.…”

Omicron BA.2 Lineage, the “Stealth” Variant: Is It Truly a Silent Epidemic? A Literature Review

“…Similarly, double-vaccination-induced neutralization showed a 17-fold reduction when comparing BA.1 or BA.3 to B.1 (BA.1 p = 0.0020; BA.3 p = 0.0020), whereas the neutralization of BA.2 was just 9-fold reduced (p = 0.0020) [23]. A study currently under revision has proposed a mechanism to explain the BA.2 lineage's broad immune escape: the S371L/F mutation in the RBD seems to induce dynamic conformational changes of the spike trimer, reducing antibody neutralization without detrimental effect on viral fitness [25]. However, according to another analysis, the immune escape capacity of BA.2 seems to be less effective in comparison to that of BA.1 [26].…”

Complexity of Viral Epitope Surfaces as Evasive Targets for Vaccines and Therapeutic Antibodies

“…This surprising result led us to suspect that the S371L/F mutations mediate their effect through a feature of epitope complexity that has not yet been described for SARS-CoV-2 spike. We hypothesized that epitope complexity at play is likely a combination of structural dynamics and N-glycan interactions, most likely mediated via a novel interaction between L/F371 and the N343 N-glycan (81). More specifically, we hypothesized the novel interaction may modulate the dynamic spike opening process via the previously described "glycan gate" function of the N343 glycan (83), in which the N343 glycan releases the adjacent RBD promoter from the three RBD-down (spike closed) conformation and then subsequently pushes the released RBD into the RBD-up state.…”

“…Further, viral surface protein dynamics can drive epitope complexity, as epitopes on dynamic surfaces may present in diverse conformational states that affect antibody accessibility as observed for certain SARS-CoV-2 receptor binding domain (RBD). RBD epitopes are exposed variably across spike conformational states, wherein relative state occupancy varies across variants and state occupancy shifts can plausibly result in escape from antibodies targeting epitopes only accessible in "open" states (81)(82)(83). Therefore, it is important to analyze EPIs in the context of epitope complexity that extends beyond sequence conservation, which is often used to assess similarity of epitope surfaces across viral strains through evolution and antigenic drift.…”

“…Specifically, we present examples of network and structure-based analyses of complex viral epitope surfaces from the standpoint of improving design and repurposing of therapeutic antibodies and mapping antigenic drift, as performed by us and others. These approaches include functional characterization of a cross-neutralizing Henipavirus antibody (92), developing a framework for antibody-glycan interactions (63), modeling N-glycan topology toward repurposing the antibody 2G12 (93), mapping antigenic orthogonality between and within overlapping RBD epitopes (51), and rapidly mapping the mutational landscape of the Omicron sub-variants (52,81).…”