title: Predicting the effect of a point mutation on a protein fold: the villin and advillin headpieces and their Pro62Ala mutants.
abstract: Homology modeling of unknown proteins is based on the assumption that highly similar sequences are likely to share the same fold. However, this does not provide any information on the stability of a given fold, which is ultimately determined by the subtle interplay of enthalpic and entropic contributions. Herein it is shown that ab initio atomistic simulations can be used to predict the effect of point mutations on the stability of a protein fold. The calculations indicate that the fold stabilities of two proteins of similar sequence and identical fold, the villin and advillin C-terminal headpiece fragments, are different and that the same P62A point mutation has a dramatic effect on the fold of villin but a minor one on that of advillin. These predictions were subsequently validated by NMR and CD experiments.
authors.affiliation: Department of Applied Chemistry, Nanochemistry Research Institute, Curtin University of Technology, GPO Box U1987, Perth, Western Australia 6845, Australia. piana@deshaw.com
authors.forename: Stefano
authors.initials: S
authors.lastname: Piana
authors.forename: Alessandro
authors.initials: A
authors.lastname: Laio
authors.forename: Fabrizio
authors.initials: F
authors.lastname: Marinelli
authors.forename: Marleen
authors.initials: M
authors.lastname: Van Troys
authors.forename: David
authors.initials: D
authors.lastname: Bourry
authors.forename: Christophe
authors.initials: C
authors.lastname: Ampe
authors.forename: José C
authors.initials: JC
authors.lastname: Martins
mesh_terms: D000409:Alanine / Q000737:chemistry / Q000235:genetics*; D020816:Amino Acid Motifs; D000595:Amino Acid Sequence; D002942:Circular Dichroism; D016000:Cluster Analysis; D019295:Computational Biology / Q000379:methods; D003198:Computer Simulation; D017124:Conserved Sequence; D006358:Hot Temperature; D006801:Humans; D057927:Hydrophobic and Hydrophilic Interactions; D007700:Kinetics; D008840:Microfilament Proteins / Q000138:chemical synthesis / Q000737:chemistry / Q000235:genetics*; D008958:Models, Molecular; D008969:Molecular Sequence Data; D019906:Nuclear Magnetic Resonance, Biomolecular; D017354:Point Mutation; D011487:Protein Conformation; D011489:Protein Denaturation; D017510:Protein Folding; D017433:Protein Structure, Secondary; D017386:Sequence Homology, Amino Acid; D013816:Thermodynamics
chemical_list: C114228:AVIL protein, human; D008840:Microfilament Proteins; C026615:villin; D000409:Alanine