Quantitative Characterization and Prediction of the Binding Determinants and Immune Escape Hotspots for Groups of Broadly Neutralizing Antibodies Against Omicron Variants: Atomistic Modeling of the SARS-CoV-2 Spike Complexes with Antibodies.

The growing body of experimental and computational studies suggested that the cross-neutralization antibody activity against Omicron variants may be driven by balance and tradeoff of multiple energetic factors and interaction contributions of the evolving escape hotspots involved in antigenic drift and convergent evolution. However, the dynamic and energetic details quantifying the balance and contribution of these factors, particularly the balancing nature of specific interactions formed by antibodies with the epitope residues remain scarcely characterized. In this study, we performed molecular dynamics simulations, ensemble-based deep mutational scanning of SARS-CoV-2 spike residues and binding free energy computations for two distinct groups of broadly neutralizing antibodies : E1 group (BD55-3152, BD55-3546 and BD5-5840) and F3 group (BD55-3372, BD55-4637 and BD55-5514). Using these approaches, we examine the energetic determinants by which broadly potent antibodies can largely evade immune resistance. Our analysis revealed the emergence of a small number of immune escape positions for E1 group antibodies that correspond to R346 and K444 positions in which the strong van der Waals and interactions act synchronously leading to the large binding contribution. According to our results, E1 and F3 groups of Abs effectively exploit binding hotspot clusters of hydrophobic sites critical for spike functions along with selective complementary targeting of positively charged sites that are important for ACE2 binding. Together with targeting conserved epitopes, these groups of antibodies can lead to the expanded neutralization breadth and resilience to antigenic shift associated with viral evolution. The results of this study and the energetic analysis demonstrate excellent qualitative agreement between the predicted binding hotspots and critical mutations with respect to the latest experiments on average antibody escape scores. We argue that E1 and F3 groups of antibodies targeting binding epitopes may leverage strong hydrophobic interactions with the binding epitope hotspots critical for the spike stability and ACE2 binding, while escape mutations tend to emerge in sites associated with synergistically strong hydrophobic and electrostatic interactions.