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      Protein folding, misfolding and aggregation: the importance of two-electron stabilizing interactions

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      Author(s)
      Cieplak, A. S.
      Date
      2017
      Source Title
      PLoS ONE
      Print ISSN
      1932-6203
      Publisher
      Public Library of Science
      Volume
      12
      Issue
      9
      Pages
      1 - 71
      Language
      English
      Type
      Article
      Item Usage Stats
      240
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      163
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      Abstract
      Proteins associated with neurodegenerative diseases are highly pleiomorphic and may adopt an all-α-helical fold in one environment, assemble into all-β-sheet or collapse into a coil in another, and rapidly polymerize in yet another one via divergent aggregation pathways that yield broad diversity of aggregates’ morphology. A thorough understanding of this behaviour may be necessary to develop a treatment for Alzheimer’s and related disorders. Unfortunately, our present comprehension of folding and misfolding is limited for want of a physicochemical theory of protein secondary and tertiary structure. Here we demonstrate that electronic configuration and hyperconjugation of the peptide amide bonds ought to be taken into account to advance such a theory. To capture the effect of polarization of peptide linkages on conformational and H-bonding propensity of the polypeptide backbone, we introduce a function of shielding tensors of the Cα atoms. Carrying no information about side chain-side chain interactions, this function nonetheless identifies basic features of the secondary and tertiary structure, establishes sequence correlates of the metamorphic and pH-driven equilibria, relates binding affinities and folding rate constants to secondary structure preferences, and manifests common patterns of backbone density distribution in amyloidogenic regions of Alzheimer’s amyloid β and tau, Parkinson’s α-synuclein and prions. Based on those findings, a split-intein like mechanism of molecular recognition is proposed to underlie dimerization of Aβ, tau, αS and PrPC, and divergent pathways for subsequent association of dimers are outlined; a related mechanism is proposed to underlie formation of PrPSc fibrils. The model does account for: (i) structural features of paranuclei, off-pathway oligomers, non-fibrillar aggregates and fibrils; (ii) effects of incubation conditions, point mutations, isoform lengths, small-molecule assembly modulators and chirality of solid-liquid interface on the rate and morphology of aggregation; (iii) fibril-surface catalysis of secondary nucleation; and (iv) self-propagation of infectious strains of mammalian prions. © 2017 Andrzej Stanisław Cieplak. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
      Keywords
      Alpha synuclein
      Oligomer
      Prion protein
      Tau protein
      Amyloid beta protein
      Protein aggregate
      SNCA protein
      Alzheimer disease
      Binding affinity
      Catalysis
      Conjugation
      Dimerization
      Electron
      Human
      Hydrogen bond
      Molecular recognition
      Parkinson disease
      pH
      Point mutation
      Polarization
      Prion
      Protein aggregation
      Protein conformation
      Protein folding
      Protein interaction
      Protein misfolding
      Protein secondary structure
      Protein tertiary structure
      Animal
      Chemistry
      Genetics
      Metabolism
      Molecular model
      Protein domain
      Protein multimerization
      PrPSc Proteins
      Permalink
      http://hdl.handle.net/11693/37017
      Published Version (Please cite this version)
      http://dx.doi.org/10.1371/journal.pone.0180905
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      • Department of Chemistry 677
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