title: Molecular dynamics of mouse and Syrian hamster PrP: implications for activity.
abstract: Molecular dynamics computer simulations have been performed on Mouse (Mo) and Syrian Hamster (SHa) prion proteins. These proteins differ, primarily, in that the SHa form incorporates additional residues at the C-terminus and also includes a segment of the unstructured N-terminal region that is required for infectivity. The 1-ns simulations have been analyzed by using a combination of dynamical cross-correlation maps, residue-residue contact plots, digital filtering, and residue-based root-mean-square deviations. The results show that the extra residues present in the SHa form at the C- and N-termini produce changes in the stability of key regions of the protein. The loop region between strand S2 and helix B that contains part of the proposed discontinuous binding site for the chaperone, protein X, is found to be more stable in SHa than in the Mo protein; these results are consistent with the NMR data of James et al. (James et al. Proc Natl Acad Sci USA 1997;94:10086-10091). In addition, a degree of flexibility within the region between and including strand S1 and helix A is also shown in SHa, which is not present in the Mo form; the cross-correlation maps suggest that this is a consequence of the additional unstructured N-terminal region. Furthermore, the extra residues in the N-terminal region of SHa are found to form a beta-bridge with the beta-sheet, within which critical point mutations associated with prion diseases lie. The implications of these results for the conformational interconversion pathway of the prion protein are discussed.
authors.affiliation: Department of Chemistry, University of Southampton, Highfield, United Kingdom.
authors.forename: O G
authors.initials: OG
authors.lastname: Parchment
authors.forename: J W
authors.initials: JW
authors.lastname: Essex
mesh_terms: D000595:Amino Acid Sequence; D000818:Animals; D003198:Computer Simulation; D006224:Cricetinae; D008647:Mesocricetus; D051379:Mice; D008958:Models, Molecular; D008969:Molecular Sequence Data; D017354:Point Mutation; D018621:PrPC Proteins / Q000737:chemistry* / Q000235:genetics; D018620:PrPSc Proteins / Q000737:chemistry* / Q000235:genetics; D017434:Protein Structure, Tertiary
chemical_list: D018621:PrPC Proteins; D018620:PrPSc Proteins