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dc.contributor.authorCieplak, A. S.en_US
dc.date.accessioned2018-04-12T11:00:11Z
dc.date.available2018-04-12T11:00:11Z
dc.date.issued2017en_US
dc.identifier.issn1932-6203
dc.identifier.urihttp://hdl.handle.net/11693/37017
dc.description.abstractProteins 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.en_US
dc.language.isoEnglishen_US
dc.source.titlePLoS ONEen_US
dc.relation.isversionofhttp://dx.doi.org/10.1371/journal.pone.0180905en_US
dc.subjectAlpha synucleinen_US
dc.subjectOligomeren_US
dc.subjectPrion proteinen_US
dc.subjectTau proteinen_US
dc.subjectAmyloid beta proteinen_US
dc.subjectProtein aggregateen_US
dc.subjectSNCA proteinen_US
dc.subjectAlzheimer diseaseen_US
dc.subjectBinding affinityen_US
dc.subjectCatalysisen_US
dc.subjectConjugationen_US
dc.subjectDimerizationen_US
dc.subjectElectronen_US
dc.subjectHumanen_US
dc.subjectHydrogen bonden_US
dc.subjectMolecular recognitionen_US
dc.subjectParkinson diseaseen_US
dc.subjectpHen_US
dc.subjectPoint mutationen_US
dc.subjectPolarizationen_US
dc.subjectPrionen_US
dc.subjectProtein aggregationen_US
dc.subjectProtein conformationen_US
dc.subjectProtein foldingen_US
dc.subjectProtein interactionen_US
dc.subjectProtein misfoldingen_US
dc.subjectProtein secondary structureen_US
dc.subjectProtein tertiary structureen_US
dc.subjectAnimalen_US
dc.subjectChemistryen_US
dc.subjectGeneticsen_US
dc.subjectMetabolismen_US
dc.subjectMolecular modelen_US
dc.subjectProtein domainen_US
dc.subjectProtein multimerizationen_US
dc.subjectPrPSc Proteinsen_US
dc.titleProtein folding, misfolding and aggregation: the importance of two-electron stabilizing interactionsen_US
dc.typeArticleen_US
dc.departmentDepartment of Chemistryen_US
dc.citation.spage1en_US
dc.citation.epage71en_US
dc.citation.volumeNumber12en_US
dc.citation.issueNumber9en_US
dc.identifier.doi10.1371/journal.pone.0180905en_US
dc.publisherPublic Library of Scienceen_US


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