Structure-based energetics of protein interfaces guides foot-and-mouth disease virus vaccine design
Kotecha, Abhay; Seago, Julian; Scott, Katherine Anne; Burman, Alison; Loureiro, Silvia; Ren, Jingshan; Porta, Claudine; Ginn, Helen M.; Jackson, Terry; Perez-Martin, Eva; Siebert, C. Alistair; Paul, Guntram; Huiskonen, Juha T.; Jones, Ian M.; Esnouf, Robert M.; Fry, Elizabeth E.; Maree, Francois Frederick; Charleston, Bryan; Stuart, David I.
Virus capsids are primed for disassembly, yet capsid integrity is key to generating a protective immune response. Foot-and-mouth
disease virus (FMDV) capsids comprise identical pentameric protein subunits held together by tenuous noncovalent interactions
and are often unstable. Chemically inactivated or recombinant empty capsids, which could form the basis of future vaccines, are
even less stable than live virus. Here we devised a computational method to assess the relative stability of protein-protein interfaces
and used it to design improved candidate vaccines for two poorly stable, but globally important, serotypes of FMDV: O and SAT2.
We used a restrained molecular dynamics strategy to rank mutations predicted to strengthen the pentamer interfaces and applied
the results to produce stabilized capsids. Structural analyses and stability assays confirmed the predictions, and vaccinated animals
generated improved neutralizing-antibody responses to stabilized particles compared to parental viruses and wild-type capsids.