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Long-Range Regulation Of Neurodegenerative Self-Assembly In Partially Folded Amyloid-Forming Helical Peptides (Poster)

Neurodegenerative self-assembly of amyloid-forming peptides amyloid-beta42 (Ab42) and alpha-synuclein (aS) through hydrophobic interactions is implicated in Alzheimer’s and Parkinson’s diseases, respectively. Although the native states of these peptide monomers are intrinsically disordered in water, their aggregation propensity have been correlated with the formation of short lived, partially folded helical conformers via helix-helix associations to helical oligomers, finally leading to formation of insoluble fibrils in vivo. Given the challenge in characterising the transient populations of helical intermediates by spectroscopy, little is known about what causes partially folded helical monomers of Ab42 and aS to be so aggregation-prone, compared to the fully folded helical or fully unfolded conformations. We comprehensively map the helical conformational sub-spaces of Ab42 and aS using extensive molecular dynamics computer simulations, utilizing a range of physical models. Our computed cross-correlation network analyses uncover a shared feature of long-range concerted coupling between the partially folded helical regions of the central hydrophobic domains and the disordered terminal ends (N-terminus in Ab42 and C-terminus in aS). The absence of such intra-peptide modulation within the calculated helically folded and unfolded conformational spaces identifies long-range regulation of the hydrophobic core regions by the termini, which may provide a rationale for the rapid aggregation of these partially folded states by hydrophobic interactions. Thus, we propose a new means of regulating helical self-assembly by targeting sites far from the hydrophobic core regions.