Protein folding, misfolding and aggregation: the importance of two-electron stabilizing interactions
Cieplak, A. S.
Public Library of Science
1 - 71
Item Usage Stats
MetadataShow full item record
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.
Amyloid beta protein
Protein secondary structure
Protein tertiary structure
Published Version (Please cite this version)http://dx.doi.org/10.1371/journal.pone.0180905
Showing items related by title, author, creator and subject.
TRIB2 confers resistance to anti-cancer therapy by activating the serine/threonine protein kinase AKT Hill, R.; Madureira, P. A.; Ferreira, B.; Baptista, I.; Machado, S.; Colaço, L.; Dos Santos, M.; Liu, N.; Dopazo, A.; Ugurel, S.; Adrienn, A.; Kiss-Toth, E.; Isbilen, M.; Gure, A. O.; Link, W. (Nature Publishing Group, 2017)Intrinsic and acquired resistance to chemotherapy is the fundamental reason for treatment failure for many cancer patients. The identification of molecular mechanisms involved in drug resistance or sensitization is imperative. ...
Mutation in TOR1AIP1 encoding LAP1B in a form of muscular dystrophy: A novel gene related to nuclear envelopathies Kayman-Kurekci G.; Talim, B.; Korkusuz P.; Sayar, N.; Sarioglu, T.; Oncel I.; Sharafi P.; Gundesli H.; Balci-Hayta, B.; Purali, N.; Serdaroglu-Oflazer P.; Topaloglu H.; Dincer P. (Elsevier Ltd, 2014)We performed genome-wide homozygosity mapping and mapped a novel myopathic phenotype to chromosomal region 1q25 in a consanguineous family with three affected individuals manifesting proximal and distal weakness and atrophy, ...
Saraç Ö.S.; Atalay V.; Cetin-Atalay, R. (2010)Functional protein annotation is an important matter for in vivo and in silico biology. Several computational methods have been proposed that make use of a wide range of features such as motifs, domains, homology, structure ...