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2017 ; 12
(9
): e0180905
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Protein folding, misfolding and aggregation: The importance of two-electron
stabilizing interactions
#MMPMID28922400
Cieplak AS
PLoS One
2017[]; 12
(9
): e0180905
PMID28922400
show ga
Proteins associated with neurodegenerative diseases are highly pleiomorphic and
may adopt an all-?-helical fold in one environment, assemble into all-?-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 C? 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 ?
and tau, Parkinson's ?-synuclein and prions. Based on those findings, a
split-intein like mechanism of molecular recognition is proposed to underlie
dimerization of A?, tau, ?S 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.
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