Impact of New Variants on SAR-CoV-2 Infectivity and Neutralization: A Molecular Assessment of the Alterations in the Spike-Host Protein Interactions

Background: The emergence of SARS-CoV-2 variants, especially the Delta variant that became the dominant variant in the US and UK within weeks, necessitates a rational assessment of their impact on the recognition and potential neutralization of the virus by the host cells. Method: We carried out an extensive comparative analysis of the interactions of the variants with cognate molecules (ACE2, furin, or heparin), neutralizing nanobodies (Nbs) and monoclonal antibodies (mAbs) using in silico models and simulations, in addition to Nb-binding assays conducted for the Delta variant. Findings: The results shed light on the molecular origin of experimental observations and help make predictions on the impact of variants that have not been experimentally established to date. Notably, the increased ACE2-binding affinity of variants containing the N501Y or E484K mutations can be traced to the time-dependent disruption and/or formation of interfacial salt bridges, not necessarily apparent from structural models but detected by extensive molecular dynamics simulations. The analysis also explains why the South African variant has an increased tendency to evade mAbs such as REGN10933 (casirivimab), LY-CoV016 (etesevimab), LY-CoV555 (bamlanivimab), BD23, and C105 or the nanobody H11-H4, while being insensitive to others including REGN10987 (imdevimab). Simulations also show the distinctive response of the Delta variant to different antibodies, including the minimal effect on the neutralizing activity of the nanobody Nb20, which is confirmed by our experiments. This contrasts the reduction in the potency of the Eli Lilly mAb LY-CoV555.Interpretations. Of interest are critical substitutions T478K, L452R and P681R in the Delta variant that may explain its increased transmissibility. The former two tend to enhance the associations with ACE2 and heparin. The third, P681R, located at a putative superantigenic site, plays a critical role in enhancing the efficiency of proteolytic cleavage and thus accelerating viral entry, because the polybasic wildtype motif P 681 RRAR serving as recognition site for the polyacidic binding epitope of furin-like proteolytic enzymes is rendered even more basic and attractive upon this substitution. The distinctive behavior of the variants vis-a-vis different types of Abs highlights the significance of carrying out full-atomic structure- and dynamics-dependent studies for assessing the specific response of different Abs to newly emerging variants. Funding: National Institutes of Health (NIGMS and NAIAD awards) and a MolSSI COVID-19 Seed Software Fellowship. Declaration of Interest: Ethical Approval