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.

A growing body of experimental and computational studies suggests that the cross-neutralization antibody activity against Omicron variants may be driven by the balance and tradeoff between 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 epitope residues, remain largely uncharacterized. In this study, we performed molecular dynamics simulations, an ensemble-based deep mutational scanning of SARS-CoV-2 spike residues, and binding free energy computations for two distinct groups of broadly neutralizing antibodies: the E1 group (BD55-3152, BD55-3546, and BD5-5840) and the F3 group (BD55-3372, BD55-4637, and BD55-5514). Using these approaches, we examined 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 the 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, the E1 and F3 groups of Abs effectively exploit binding hotspot clusters of hydrophobic sites that are critical for spike functions along with the selective complementary targeting of positively charged sites that are important for ACE2 binding. Together with targeting conserved epitopes, these groups of antibodies can lead expand the breadth and resilience of neutralization to the antigenic shifts 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 the E1 and F3 groups of antibodies targeting binding epitopes may leverage strong hydrophobic interactions with the binding epitope hotspots that are critical for the spike stability and ACE2 binding, while escape mutations tend to emerge in sites associated with synergistically strong hydrophobic and electrostatic interactions.