Computational Study of Antibody Binding to SARS-CoV-2 Variants

Background/Objectives: The unprecedented structural and binding data for antibodies to the SARS-CoV-2 virus taken together with the mutations for the spike protein allows for a broad simulation study of antibody-spike protein binding. This provides an understanding of the co-evolution of human immunity and viral immunity escape. Methods: We utilized the YASARA molecular dynamics program to generate initial structures and simulate to equilibration for six SARS-CoV-2 variants and ten different antibodies sampling two different binding regions to the receptor binding domain of the spike (especially for the Class I antibodies in the same part of the spike that attaches to the ACE2 receptor protein) and one to the N-terminal domain of the spike. Starting structures for antibody binding to variant spike protein domains are perturbatively achieved through point mutations and insertions/deletions in the YASARA program. We employed YASARA to measure interfacial hydrogen bound counts between antibodies and variant spike proteins and the HawkDock MMGBSA program to characterize trends in binding energies with mutation for four of the antibodies. We utilized the VMD program to analyze the time course of hydrogen bond populations. Results: As seen in previous studies, interfacial hydrogen bond counts serve as an excellent proxy for binding energies without the large systematic error inherent in the latter. We find that there is generally a decline in antibody binding strength, as measured by interfacial hydrogen bond counts, with viral evolution, but that a modest re-entrance of binding strength is present for most antibodies studied. Generically, the antibody heavy chain binds more strongly to the spike protein, though for approximately half the antibodies the light chain binding strength converges to the heavy chain strength with viral evolution. Conclusions: The key conclusion is that the identified re-entrant immunity, speculatively arising from a balancing of maintenance of ACE2-spike binding while escaping antibodies through mutation, allows for some maintenance and even strengthening of immunity for later viral strains from early infection or vaccination.