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Molecular dynamics simulations indicate a possible role of parallel beta-helices in seeded aggregation of poly-Gln.

ABSTRACT: The molecular structures of amyloid fibers characterizing neurodegenerative diseases such as Huntington's or transmissible spongiform encephalopathies are unknown. Recently, x-ray diffraction patterns of poly-Gln fibers and electron microscopy images of two-dimensional crystals formed from building blocks of prion rods have suggested that the corresponding amyloid fibers are generated by the aggregation of parallel beta-helices. To explore this intriguing concept, we study the stability of small beta-helices in aqueous solution by molecular dynamics simulations. In particular, for the Huntington aggregation nucleus, which is thought to be formed of poly-Gln polymers, we show that three-coiled beta-helices are unstable at the suggested circular geometries and stable at a triangular shape with 18 residues per coil. Moreover, we demonstrate that individually unstable two-coiled triangular poly-Gln beta-helices become stabilized upon dimerization, suggesting that seeded aggregation of Huntington amyloids requires dimers of at least 36 Gln repeats (or monomers of approximately 54 Gln) for the formation of sufficiently stable aggregation nuclei. An analysis of our results and of sequences occurring in native beta-helices leads us to the proposal of a revised model for the PrP(Sc) aggregation nucleus.

SUBMITTER: Stork M

PROVIDER: S-EPMC1305343 | biostudies-literature | 2005 Apr

REPOSITORIES: biostudies-literature

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Molecular dynamics simulations indicate a possible role of parallel beta-helices in seeded aggregation of poly-Gln.

Stork Martina M Giese Armin A Kretzschmar Hans A HA Tavan Paul P

Biophysical journal 20050121 4

The molecular structures of amyloid fibers characterizing neurodegenerative diseases such as Huntington's or transmissible spongiform encephalopathies are unknown. Recently, x-ray diffraction patterns of poly-Gln fibers and electron microscopy images of two-dimensional crystals formed from building blocks of prion rods have suggested that the corresponding amyloid fibers are generated by the aggregation of parallel beta-helices. To explore this intriguing concept, we study the stability of small ...[more]

PMID: 15665127

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Project description:BackgroundAnalysis of known protein structures reveals that identical sequence fragments in proteins can adopt different secondary structure conformations. The extent of this conformational diversity is influenced by various factors like the intrinsic sequence propensity, sequence context and other environmental factors such as pH, site directed mutations or alteration of the binding ligands. Understanding the mechanism by which the environment affects the structural ambivalence of these peptides has potential implications for protein design and reliable local structure prediction algorithms. Identification of the structurally ambivalent sequence fragments and determining the rules which dictate their conformational preferences play an important role in understanding the conformational changes observed in misfolding diseases. However, a systematic classification of their intrinsic sequence patterns or a statistical analysis of their properties and sequence context in relation to the origin of their structural diversity have largely remained unexplored.ResultsIn this work, the conformational variability of α-helices is studied by mapping sequences from the non-redundant database to identical sequences across all classes of the SCOP (Structural Classification of Proteins) database. Some helices retain their conformations when mapped in the SCOP database while others exhibit a complete/partial switch to non-helical conformations. The results clearly depict the differences in the propensities of amino acids for the variable and conserved helices. Sequences flanking these ambivalent sequence fragments have anisotropic propensities at the N- and C-termini. This structural variability is depicted by molecular dynamics simulations in explicit solvent, which show that the short conserved helices retain their conformations while their longer counterparts fray into two or more shorter helices. Variable helices in the non-redundant database exhibit a trend of retaining helical conformations while their corresponding non-helical conformations in SCOP database show large deviations from their respective initial structures by adopting partial or full helical conformations. Partially ambivalent helices are also found to retain their respective conformations.ConclusionsAll sequence fragments which show structural diversity in different proteins of the non-redundant database are investigated. The final conformation of these ambivalent sequences are dictated by a fine tuning of their intrinsic sequence propensity and the anisotropic amino acid propensity of the flanking sequences. This analysis may unravel the connection between diverse secondary structures, which conserve the overall structural fold of the protein thus determining its function.

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Molecular dynamics simulations indicate a possible role of parallel beta-helices in seeded aggregation of poly-Gln.

Publications

Molecular dynamics simulations indicate a possible role of parallel beta-helices in seeded aggregation of poly-Gln.

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