Protein folding, misfolding and aggregation: the importance of two-electron stabilizing interactions
Author(s)
Date
2017Source Title
PLoS ONE
Print ISSN
1932-6203
Publisher
Public Library of Science
Volume
12
Issue
9
Pages
1 - 71
Language
English
Type
ArticleItem Usage Stats
240
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views
163
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downloads
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 synucleinOligomer
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/11693/37017Published Version (Please cite this version)
http://dx.doi.org/10.1371/journal.pone.0180905Collections
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