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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.

Original publication




Journal article


Nat Struct Mol Biol

Publication Date





788 - 794


Animals, Antibodies, Neutralizing, Base Sequence, Capsid Proteins, Computational Biology, Cryoelectron Microscopy, Crystallography, X-Ray, Drug Design, Enzyme-Linked Immunosorbent Assay, Foot-and-Mouth Disease, Foot-and-Mouth Disease Virus, Microscopy, Electron, Models, Molecular, Molecular Dynamics Simulation, Molecular Sequence Data, Protein Interaction Domains and Motifs, Reverse Transcriptase Polymerase Chain Reaction, Sequence Analysis, DNA, Viral Vaccines