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Predicting the effect of a point mutation on a protein fold: the villin and advillin headpieces and their Pro62Ala mutants |
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| Authors: | Piana Stefano Laio Alessandro Marinelli Fabrizio Van Troys Marleen Bourry David Ampe Christophe Martins José C |
| Institution: | 1 Department of Applied Chemistry, Nanochemistry Research Institute, Curtin University of Technology, GPO Box U1987, Perth, Western Australia 6845, Australia 2 International School for Advanced Studies, Via Beirut 2-4, 34014 Trieste, Italy 3 V.I.B. Department of Medical Protein Chemistry and Department of Biochemistry, Ghent University, A. Baertsoenkaai 3, B-9000 Ghent, Belgium 4 NMR and Structure Analysis Unit, Department of Organic Chemistry, Ghent University, Krijgslaan 281 S4, B-9000 Ghent, Belgium |
| 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. |
| Keywords: | WT wild type cHP C-terminal headpiece MD molecular dynamics BE bias exchange CV collective variable NOE nuclear Overhauser enhancement NOESY nuclear Overhauser enhancement spectroscopy TRPZIP tryptophan zipper TRPC tryptophan cage NPT constant temperature and pressure |
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