title: Dry amyloid fibril assembly in a yeast prion peptide is mediated by long-lived structures containing water wires.
abstract: Amyloid-like fibrils from a number of small peptides that are unrelated by sequence adopt a cross-β-spine in which the two sheets fully interdigitate to create a dry interface. Formation of such a dry interface is usually associated with self-assembly of extended hydrophobic surfaces. Here we investigate how a dry interface is created in the process of protofilament formation in vastly different sequences using two amyloidogenic peptides, one a polar sequence from the N terminus of the yeast prion Sup35 and the other a predominantly hydrophobic sequence from the C terminus of Aβ-peptide. Using molecular dynamics simulations with three force fields we show that spontaneous formation of two ordered one-dimensional water wires in the pore between the two sheets of the Sup35 protofilaments results in long-lived structures, which are stabilized by a network of hydrogen bonds between the water molecules in the wires and the polar side chains in the β-sheet. Upon decreasing the stability of the metastable structures, water molecules are expelled resulting in a helically twisted protofilament in which side chains from a pair of β-strands in each sheet pack perfectly resulting in a dry interface. Although drying in hydrophobically dominated interfaces is abrupt, resembling a liquid to vapor transition, we find that discrete transitions between the liquid to one-dimensional ordered water in the nanopore enclosed by the two β-sheets to dry interface formation characterizes protofilament assembly in the yeast prions. Indeed, as the two sheets of the hydrophobic Aβ-sequence approach each other, fibril formation and expulsion of water molecules occur rapidly and nearly simultaneously.
authors.affiliation: Department of Chemistry and Biochemistry, University of Maryland, Biophysics Program, Institute for Physical Science and Technology, College Park, MD 20742, USA.
authors.forename: Govardhan
authors.initials: G
authors.lastname: Reddy
authors.forename: John E
authors.initials: JE
authors.lastname: Straub
authors.forename: D
authors.initials: D
authors.lastname: Thirumalai
mesh_terms: D000682:Amyloid / Q000737:chemistry*; D005656:Fungal Proteins / Q000737:chemistry*; D006860:Hydrogen Bonding; D008958:Models, Molecular; D056004:Molecular Dynamics Simulation; D010455:Peptides / Q000737:chemistry*; D011328:Prions / Q000737:chemistry*; D017433:Protein Structure, Secondary; D055672:Static Electricity; D014867:Water / Q000737:chemistry*
chemical_list: D000682:Amyloid; D005656:Fungal Proteins; D010455:Peptides; D011328:Prions; D014867:Water