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

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.

Structure of the Hydrophobic Core Determines the 3D Protein Structure—Verification by Single Mutation Proteins

“…External factors are also taken into account as affecting structural changes in proteins [22][23][24][25]. Oligomerization is also recognized as a phenomenon that stimulates the adoption of different structural forms of metamorphic proteins [26].…”

Tau Inclusions in Alzheimer's, Chronic Traumatic Encephalopathy and Pick's Disease. A Speculation on How Differences in Backbone Polarization Underlie Divergent Pathways of Tau Aggregation

“…Unfortunately, our current understanding of protein folding and misfolding is limited for want of a physicochemical theory of protein secondary and tertiary structure (Baldwin and Rose, 1999). Recognizing these limitations, an attempt was recently made to construct such a theory, using the PMO theory-informed approach and focusing on the electronic configuration and hyperconjugation of the peptide amide bonds (Cieplak, 2017). To capture the effect of polarization of peptide linkages on the conformational and H-bonding propensity of the polypeptide backbone, a function of the NMR shielding tensors of the C α atoms was introduced as the folding potential function FP i .…”

“…The FP i function proved to be an effective tool to investigate conformational behavior of the intrinsically disordered and pleiomorphic proteins, revealing a common pattern of backbone density distribution in the amyloidogenic regions of several highly pleiomorphic proteins associated with neurodegenerative diseases: amyloid beta Aβ, tau, α-synuclein αS, and mammalian prions PrP C . A common molecular model of aggregation of these proteins was consequently proposed (Cieplak, 2017).…”

“…The folding potential function FP i is a function of the NMR shielding tensors of the C α atoms, σ (C α ) Xaa , which were obtained by quantum mechanical modeling of protein secondary structure. The calculations were carried out using the oligopeptides AcGXaaGGGNH 2 and AcGGGGGXaaNHMe as the models of the 3 10 -helix and the hairpin with the type Ib reverse turn, respectively, at the B3LYP/D95 ** level of the theory [Gaussian 98, Revisions A.3, A.7, A11.2 (Frisch et al, 1998)], according to the protocol described previously in Cieplak (2017). The canonical and covalently modified residues Xaa (the L-amino acid series) of the hexapeptide hairpin and the pentapeptide helix were systematically varied, taking into account side chain conformations (Kyte, 1995) and ionization state when appropriate, to yield the total of 141 congener structures.…”

Mutational analysis of the essential lipopolysaccharide-transport protein LptH of Pseudomonas aeruginosa to uncover critical oligomerization sites

“…Furthermore, each strand forms H-bonds with the adjacent strand (β1 with β6 and β2 with β15). These lateral H-bonds were peculiar for the β-jellyroll fold 18 . Furthermore, we observed a H-bond between the polar side chains of Arg 34 (β1) and Asp 165 (β16), and another one between the polar side chains of Glu 41 (β2) and Asn 148 (β15) (Fig.…”