title: Molecular origin of Gerstmann-Sträussler-Scheinker syndrome: insight from computer simulation of an amyloidogenic prion peptide.
abstract: Prion proteins become pathogenic through misfolding. Here, we characterize the folding of a peptide consisting of residues 109-122 of the Syrian hamster prion protein (the H1 peptide) and of a more amyloidogenic A117V point mutant that leads in humans to an inheritable form of the Gerstmann-Sträussler-Scheinker syndrome. Atomistic molecular dynamics simulations are performed for 2.5 μs. Both peptides lose their α-helical starting conformations and assume a β-hairpin that is structurally similar in both systems. In each simulation several unfolding/refolding events occur, leading to convergence of the thermodynamics of the conformational states to within 1 kJ/mol. The similar stability of the β-hairpin relative to the unfolded state is observed in the two peptides. However, substantial differences are found between the two unfolded states. A local minimum is found within the free energy unfolded basin of the A117V mutant populated by misfolded collapsed conformations of comparable stability to the β-hairpin state, consistent with increased amyloidogenicity. This population, in which V117 stabilizes a hydrophobic core, is absent in the wild-type peptide. These results are supported by simulations of oligomers showing a slightly higher stability of the associated structures and a lower barrier to association for the mutated peptide. Hence, a single point mutation carrying only two additional methyl groups is here shown to be responsible for rather dramatic differences of structuring within the unfolded (misfolded) state.
authors.affiliation: Department of Chemistry, Chemical Engineering and Materials, University of L'Aquila, L'Aquila, Italy. daidone@caspur.it
authors.forename: Isabella
authors.initials: I
authors.lastname: Daidone
authors.forename: Alfredo
authors.initials: A
authors.lastname: Di Nola
authors.forename: Jeremy C
authors.initials: JC
authors.lastname: Smith
mesh_terms: D000595:Amino Acid Sequence; D000682:Amyloid / Q000378:metabolism*; D000818:Animals; D003198:Computer Simulation; D006224:Cricetinae; D016098:Gerstmann-Straussler-Scheinker Disease / Q000378:metabolism*; D008969:Molecular Sequence Data; D050505:Mutant Proteins / Q000737:chemistry / Q000378:metabolism; D010455:Peptides / Q000737:chemistry / Q000378:metabolism*; D011328:Prions / Q000737:chemistry / Q000378:metabolism*; D017510:Protein Folding; D020836:Protein Structure, Quaternary; D017433:Protein Structure, Secondary; D012997:Solvents / Q000737:chemistry; D013816:Thermodynamics; D013997:Time Factors
chemical_list: D000682:Amyloid; D050505:Mutant Proteins; D010455:Peptides; D011328:Prions; D012997:Solvents