Abstract
Neurodegeneration involves abnormal aggregation of intrinsically disordered amyloidogenic peptides (IDPs), usually mediated by hydrophobic protein-protein interactions. There is mounting evidence that formation of α-helical intermediates is an early event during self-assembly of amyloid-β42 (Aβ42) and α-synuclein (αS) IDPs in Alzheimer’s and Parkinson’s disease pathogenesis, respectively. However, the driving force behind on-pathway molecular assembly of partially folded helical monomers into helical oligomers assembly remains unknown. Here, we employ extensive molecular dynamics simulations to sample the helical conformational sub-spaces of monomeric peptides of both Aβ42 and αS. Our computed free energies, population shifts, and dynamic cross-correlation network analyses reveal a common feature of long-range intra-peptide modulation of partial helical folds of the amyloidogenic central hydrophobic domains via concerted coupling with their charged terminal tails (N-terminus of Aβ42 and C-terminus of αS). The absence of such inter-domain fluctuations in both fully helical and completely unfolded (disordered) states suggests that long-range coupling regulates the dynamicity of partially folded helices, in both Aβ42 and αS peptides. The inter-domain coupling suggests a form of intra-molecular allosteric regulation of the aggregation trigger in partially folded helical monomers. This approach could be applied to study the broad range of amyloidogenic peptides, which could provide a new path to curbing pathogenic aggregation of partially folded conformers into oligomers, by inhibition of sites far from the hydrophobic core.
Highlights
Protein conformational disorders including Alzheimer’s (AD) and Parkinson’s disease (PD) present the hallmark features of misfolding, self-assembly, and accumulation of monomeric precursor peptides known as intrinsically disordered proteins (IDPs) or amyloidogenic peptides such as amyloid-β, Aβ and α-synuclein, αS[1]
The complete helically folded states in our equilibrium MD simulations (EMD) simulations record a high percentage of helices
In light of the experimental evidences that early oligomerization of some amyloidogenic intrinsically disordered amyloidogenic peptides (IDPs) may be linked to formation of helical intermediates by helix-helix associations[3,43,58], we have extensively modelled the helical subspaces of Aβ42 and αS in order to account for the driving force behind aggregation-prone nature of partially folded helical states, and compared them to helically folded and unfolded states
Summary
Protein conformational disorders including Alzheimer’s (AD) and Parkinson’s disease (PD) present the hallmark features of misfolding, self-assembly, and accumulation of monomeric precursor peptides known as intrinsically disordered proteins (IDPs) or amyloidogenic peptides such as amyloid-β, Aβ (implicated in AD) and α-synuclein, αS (in PD)[1]. As disorder is a functional advantage for regulation at long-range[26], conformational shifts may accommodate molecular recognition of IDPs through hydrophobic interactions[27] and promote folding-induced binding or conformational selections[28] during self-assembly in many neurodegenerative diseases[29,30]. We look beyond just direct contacts in folded states and comprehensively map internal long-range communications across helically folded, partially folded and unfolded states of Aβ42 and αS peptides by computing dynamic cross-correlation networks from extensive microseconds-scale MD simulation data. The traditional CHARMM3638 protein model with CHARMM-modified TIP3P water[39] (TIP3P) and CHARMM36 with TIP4P40 parametrized for globular proteins gave as expected predominantly fully-helical folded states while the more IDP-specific CHARMM22*41 with TIP4P-D35 and Amber ff03ws[34] with the scaled TIP4P/200534,42, gave partial helical folded states together with some completely unfolded (disordered) states (see Methods). The specific scientific question is, what causes partially folded Aβ42 and αS to be so aggregation-prone, compared to the fully folded helical and unfolded conformations? In the present study, we monitor long-range coupling between domains that may influence and possibly direct, helix-helix associations of amyloidogenic peptides
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