(161b) Analysis of How Mutations Disrupt Hotspot Binding Interactions

Early during the COVID-19 pandemic, it was experimentally observed that the anti-SARS antibodies S230, M396, and 80R failed to bind to the receptor binding domain of SARS-CoV-2 despite its high degree of similarity with that of SARS-CoV. We conducted a computational analysis of why this was the case and found that loss of binding for all three antibodies was caused by the disruption of hotspot interactions rather than the introduction of detrimental contacts. This finding was not anticipated a priori, and motivated us to study the deleterious effects of point mutations in antibody-antigen interactions in general.

A set of 70 antibody-protein complexes were selected for the study based on the features of their interacting surfaces, including number of contact residues, buried surface area, and shape complementarity. The selected complexes represent the statistical diversity of these features across the ranges of values observed for experimentally-determined antibody complexes. For each complex, each of the 19 point mutations for each contacting residue in the antigens was computationally predicted and assessed. The purpose of this study was to answer the question of what happens to the interactions made by antibodies when the antigens mutate. In our presentation, we will be discussing the results of our analysis and their implications in regard to antibody interactions. Through understanding which phenomena contribute towards the loss of binding for antibodies with mutated antigens, we hope to develop strategies to prepare in advance for and respond rapidly to future emerging pandemics.