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

1 Pages Posted: 20 Feb 2020

See all articles by Shayon Bhattacharya

Shayon Bhattacharya

University of Limerick

Liang Xu

University of Limerick

Damien Thompson

University of Limerick

Date Written: January 13, 2020

Abstract

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.

Keywords: amyloid-beta, alpha-synuclein, intrinsically disordered proteins, neurodegeneration, long-range

Suggested Citation

Bhattacharya, Shayon and Xu, Liang and Thompson, Damien, Long-Range Regulation Of Neurodegenerative Self-Assembly In Partially Folded Amyloid-Forming Helical Peptides (Poster) (January 13, 2020). Proceedings of International Conference on Drug Discovery (ICDD) 2020, Available at SSRN: https://ssrn.com/abstract=3535563 or http://dx.doi.org/10.2139/ssrn.3535563

Shayon Bhattacharya (Contact Author)

University of Limerick ( email )

Castletroy, Co
Limerick
Ireland

Liang Xu

University of Limerick ( email )

Castletroy, Co
Limerick
Ireland

Damien Thompson

University of Limerick ( email )

Castletroy, Co
Limerick
Ireland

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