Computational Studies on Prion Proteins: Effect of Ala 117→Val Mutation

Abstract

Molecular dynamics calculations demonstrated the conformational change in the prion protein due to Ala 117→Val mutation, which is related to Gerstmann-Sträussler-Sheinker disease, one of the familial prion diseases. Three kinds of model structures of human and mouse prion proteins were examined: (model 1) nuclear magnetic resonance structures of human prion protein HuPrP (125-228) and mouse prion protein MoPrP (124-224), each having a globular domain consisting of three α-helices and an antiparallel β-sheet; (model 2) extra peptides including Ala 117 (109-124 in HuPrP and 109-123 in MoPrP) plus the nuclear magnetic resonance structures of model 1; and (model 3) extra peptides including Val 117 (109-124 in HuPrP and 109-123 in MoPrP) plus the nuclear magnetic resonance structures of model 1. The results of molecular dynamics calculations indicated that the globular domains of models 1 and 2 were stable and that the extra peptide in model 2 tended to form a new α-helix. On the other hand, the globular domain of model 3 was unstable, and the β-sheet region increased especially in HuPrP.