title: Computational study of the fibril organization of polyglutamine repeats reveals a common motif identified in beta-helices.
abstract: The formation of fibril aggregates by long polyglutamine sequences is assumed to play a major role in neurodegenerative diseases such as Huntington. Here, we model peptides rich in glutamine, through a series of molecular dynamics simulations. Starting from a rigid nanotube-like conformation, we have obtained a new conformational template that shares structural features of a tubular helix and of a beta-helix conformational organization. Our new model can be described as a super-helical arrangement of flat beta-sheet segments linked by planar turns or bends. Interestingly, our comprehensive analysis of the Protein Data Bank reveals that this is a common motif in beta-helices (termed beta-bend), although it has not been identified so far. The motif is based on the alternation of beta-sheet and helical conformation as the protein sequence is followed from the N to the C termini (beta-alpha(R)-beta-polyPro-beta). We further identify this motif in the ssNMR structure of the protofibril of the amyloidogenic peptide Abeta(1-40). The recurrence of the beta-bend suggests a general mode of connecting long parallel beta-sheet segments that would allow the growth of partially ordered fibril structures. The design allows the peptide backbone to change direction with a minimal loss of main chain hydrogen bonds. The identification of a coherent organization beyond that of the beta-sheet segments in different folds rich in parallel beta-sheets suggests a higher degree of ordered structure in protein fibrils, in agreement with their low solubility and dense molecular packing.
authors.affiliation: Department of Chemical Engineering, E.T.S.E.I.B.-U.P.C., Av. Diagonal 647, 08028 Barcelona, Spain. david.zanuy@upc.edu
authors.forename: David
authors.initials: D
authors.lastname: Zanuy
authors.forename: Kannan
authors.initials: K
authors.lastname: Gunasekaran
authors.forename: Arthur M
authors.initials: AM
authors.lastname: Lesk
authors.forename: Ruth
authors.initials: R
authors.lastname: Nussinov
mesh_terms: D020816:Amino Acid Motifs; D000682:Amyloid / Q000737:chemistry*; D019295:Computational Biology; D030562:Databases, Protein; D009682:Magnetic Resonance Spectroscopy; D008958:Models, Molecular; D008961:Models, Structural; D010455:Peptides / Q000737:chemistry*; D017510:Protein Folding; D017433:Protein Structure, Secondary; D013816:Thermodynamics
chemical_list: D000682:Amyloid; D010455:Peptides; C097188:polyglutamine