Title: Synergistic mutations allow for antibody resistance in respiratory syncytial virus
Project Team: Tanya Miura, Jonathan Barnes
Start Date: June 2022
This project was initially funded by the NSF EPSCoR Track II Geno-Pheno Grant to use molecular modeling to predict antibody escape variants of respiratory syncytial virus (RSV). In that work, we identified five novel mutations in the RSV fusion protein that imparted resistance to the antibody motavizumab. Interestingly, none of these mutations arise when the virus is under selective pressure, only one mutation (K272E) arises under motavizumab selection. We engineered a virus with methionine at position 272 (K272M), which is sensitive to motavizumab and requires two nucleotide changes to mutate to glutamic acid (E). When this variant was grown under motavizumab selection, a resistant variant arose, K272M/N262K. Interestingly, neither the K272M or N262K mutations individually impart motavizumab resistance.
We propose to use molecular modeling to explain how interactions between these mutations may impart resistance. This would entail three classical molecular dynamics simulations. K272M, N262K, and K272M+N262K. Trajectory analysis would follow to ascertain possible mechanisms and interactions that differ between the mutations on their own and in combination. The results of this analysis should shed light on how K272M+N262K imparts resistance when acting in concert with no observed effect on their own.