title: Structure-based energetics of protein interfaces guides foot-and-mouth disease virus vaccine design.
abstract: 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.
authors.affiliation: Division of Structural Biology, University of Oxford, Oxford, UK.
authors.forename: Abhay
authors.initials: A
authors.lastname: Kotecha
authors.affiliation: Pirbright Institute, Pirbright, UK.
authors.forename: Julian
authors.initials: J
authors.lastname: Seago
authors.affiliation: Transboundary Animal Disease Programme, Agricultural Research Council-Onderstepoort Veterinary Institute, Onderstepoort, South Africa.
authors.forename: Katherine
authors.initials: K
authors.lastname: Scott
authors.affiliation: Pirbright Institute, Pirbright, UK.
authors.forename: Alison
authors.initials: A
authors.lastname: Burman
authors.affiliation: Animal and Microbial Sciences, University of Reading, Reading, UK.
authors.forename: Silvia
authors.initials: S
authors.lastname: Loureiro
authors.affiliation: Division of Structural Biology, University of Oxford, Oxford, UK.
authors.forename: Jingshan
authors.initials: J
authors.lastname: Ren
authors.affiliation: Division of Structural Biology, University of Oxford, Oxford, UK.|Pirbright Institute, Pirbright, UK.
authors.forename: Claudine
authors.initials: C
authors.lastname: Porta
authors.affiliation: Division of Structural Biology, University of Oxford, Oxford, UK.
authors.forename: Helen M
authors.initials: HM
authors.lastname: Ginn
authors.affiliation: Pirbright Institute, Pirbright, UK.
authors.forename: Terry
authors.initials: T
authors.lastname: Jackson
authors.affiliation: Pirbright Institute, Pirbright, UK.
authors.forename: Eva
authors.initials: E
authors.lastname: Perez-Martin
authors.affiliation: Division of Structural Biology, University of Oxford, Oxford, UK.
authors.forename: C Alistair
authors.initials: CA
authors.lastname: Siebert
authors.affiliation: Merck Sharp &Dohme Animal Health, Cologne, Germany.
authors.forename: Guntram
authors.initials: G
authors.lastname: Paul
authors.affiliation: Division of Structural Biology, University of Oxford, Oxford, UK.
authors.forename: Juha T
authors.initials: JT
authors.lastname: Huiskonen
authors.affiliation: Animal and Microbial Sciences, University of Reading, Reading, UK.
authors.forename: Ian M
authors.initials: IM
authors.lastname: Jones
authors.affiliation: Division of Structural Biology, University of Oxford, Oxford, UK.
authors.forename: Robert M
authors.initials: RM
authors.lastname: Esnouf
authors.affiliation: Division of Structural Biology, University of Oxford, Oxford, UK.
authors.forename: Elizabeth E
authors.initials: EE
authors.lastname: Fry
authors.affiliation: Transboundary Animal Disease Programme, Agricultural Research Council-Onderstepoort Veterinary Institute, Onderstepoort, South Africa.|Department of Microbiology and Plant Pathology, University of Pretoria, Pretoria, South Africa.
authors.forename: Francois F
authors.initials: FF
authors.lastname: Maree
authors.affiliation: Pirbright Institute, Pirbright, UK.
authors.forename: Bryan
authors.initials: B
authors.lastname: Charleston
authors.affiliation: Division of Structural Biology, University of Oxford, Oxford, UK.|Diamond Light Source, Didcot, UK.
authors.forename: David I
authors.initials: DI
authors.lastname: Stuart
mesh_terms: D000818:Animals; D057134:Antibodies, Neutralizing / Q000097:blood; D001483:Base Sequence; D036022:Capsid Proteins / Q000737:chemistry* / Q000378:metabolism; D019295:Computational Biology / Q000379:methods; D020285:Cryoelectron Microscopy; D018360:Crystallography, X-Ray; D015195:Drug Design; D004797:Enzyme-Linked Immunosorbent Assay; D005536:Foot-and-Mouth Disease / Q000276:immunology / Q000517:prevention & control*; D029544:Foot-and-Mouth Disease Virus / Q000737:chemistry* / Q000276:immunology; D008854:Microscopy, Electron; D008958:Models, Molecular; D056004:Molecular Dynamics Simulation; D008969:Molecular Sequence Data; D054730:Protein Interaction Domains and Motifs; D020133:Reverse Transcriptase Polymerase Chain Reaction; D017422:Sequence Analysis, DNA; D014765:Viral Vaccines / Q000737:chemistry* / Q000276:immunology
chemical_list: D057134:Antibodies, Neutralizing; D036022:Capsid Proteins; D014765:Viral Vaccines