Identifying protein sites contributing to vaccine escape via statistical comparisons of short-term molecular dynamics simulations
AbstractThe identification of viral mutations that confer escape from antibodies is crucial for understanding the interplay between immunity and viral evolution. We describe a molecular dynamic (MD) based approach that scales well to a desktop computer with a high-end modern graphics processor and enables the user to identify protein sites that are prone to vaccine escape in a viral antigen. We first implemented our MD pipeline to employ site-wise calculation of Kullback-Leibler divergence in atom fluctuation over replicate sets of short-term MD production runs to compare influenza hemagglutinin’s rapid motions in the presence and absence of three well-known neutralizing antibodies. Using this simple comparative method applied to motions of viral proteins, we successfully identified in silico all previously empirically confirmed sites of escape in hemagglutinin, predetermined via selection experiments and neutralization assays. After this validation of our computational approach, we identified potential hot spot residues in the receptor binding domain (RBD) of the SARS-CoV-2 virus in the presence of COVOX-222 and S2H97 antibodies. We identified sites in the antigen-antibody interface with strong dampening of fluctuation that may indicate potential antibody escape due to single mutations. Many of these sites were found to match known sites of mutations in SARS-CoV-2 variants of concern. The determination of single sites with large effect on antigen-antibody binding interfaces is crucial to discriminating neutral variants from potential escape variants. In summary, we provide a cheap, fast, and accurate in silico method to identify and quantify potential hot spots of functional evolution in antibody binding footprints.