A DNA Threshold of Four G/C Base Pairs Drives Intramolecular <italic style="font-style: italic">β</italic>-Sheet Formation in <italic style="font-style: italic">α</italic>-Synuclein

Yi-Heng Zhang; Shuai Gong; Yu Yuan; Lei Shen

doi:10.1007/s10118-026-3674-x

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A DNA Threshold of Four G/C Base Pairs Drives Intramolecular β-Sheet Formation in α-Synuclein

RESEARCH ARTICLE | Updated：2026-06-04

- A DNA Threshold of Four G/C Base Pairs Drives Intramolecular β-Sheet Formation in α-Synuclein
- Chinese Journal of Polymer Science Vol. 44, Issue 8, Pages: 2630-2636(2026)
- Affiliations：
  
  Key Laboratory for Neurodegenerative Diseases Nanomedicine of Hubei Province; School of Chemistry, Chemical Engineering and Life Science; Institute WUT-AMU, Wuhan University of Technology, Wuhan 430070, China
- Author bio：
  
  leishen@whut.edu.cn
- Funds：
- DOI：10.1007/s10118-026-3674-x
  CLC：
- Received：08 February 2026，
  
  Accepted：18 March 2026，
  
  Online First：30 May 2026，
  
  Published：15 August 2026
- Accepted：
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Zhang, Y. H.; Gong, S.; Yuan, Y.; Shen, L. A DNA threshold of four G/C base pairs drives intramolecular β-sheet formation in α-synuclein. Chinese J. Polym. Sci. 2026, 44, 2630–2636

Yi-Heng Zhang, Shuai Gong, Yu Yuan, et al. A DNA Threshold of Four G/C Base Pairs Drives Intramolecular β-Sheet Formation in α-Synuclein[J]. Chinese Journal of Polymer Science, 2026, 44(8): 2630-2636. DOI: 10.1007/s10118-026-3674-x.
Zhang, Y. H.; Gong, S.; Yuan, Y.; Shen, L. A DNA threshold of four G/C base pairs drives intramolecular β-sheet formation in α-synuclein. Chinese J. Polym. Sci. 2026, 44, 2630–2636 DOI： 10.1007/s10118-026-3674-x.

Yi-Heng Zhang, Shuai Gong, Yu Yuan, et al. A DNA Threshold of Four G/C Base Pairs Drives Intramolecular β-Sheet Formation in α-Synuclein[J]. Chinese Journal of Polymer Science, 2026, 44(8): 2630-2636. DOI: 10.1007/s10118-026-3674-x. DOI：

摘要

Simulations revealed that

-synuclein undergoes a GC-length-dependent conformational switch: ≥4 consecutive GC pairs induce

-sheet formation

unlike AT-rich regions

implicating DNA in the regulation of protein aggregation and gene expression.

Abstract

Interactions between the intrinsically disordered protein

-synuclein (

S) and DNA are implicated in its pathological aggregation and neuronal function. However

the structural rules governing these interactions remain undefined. Through well-tempered metadynamics simulations across six distinct DNA sequence landscapes

we report a sequence-specific conformational switch in a single

S chain. While AT-rich sequences engage

S yet induce DNA duplex destabilization with minimal protein structuring

GC-rich tracts promote localized protein compaction and secondary

-sheet structure formation. Crucially

we identified a specific threshold: the presence of four or more consecutive G/C base pairs is both necessary and sufficient to nucleate the formation of a stable

intramolecular

-sheet within the N-terminal and nonamyloid component regions of the

S chain. This structured state

anchored by persistent protein-DNA contacts

is absent in shorter GC tracts or alternating sequences. In mixed-sequence contexts

the extended GC blocks function as exclusive binding hubs

minating over interactions with adjacent AT-rich regions. This GC length-dependent conformational switch provides a precise biophysical mechanism through which the DNA architecture can spatially regulate

S folding

with potential implications for its aggregation propensity and regulatory functions in gene expression.

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A DNA Threshold of Four G/C Base Pairs Drives Intramolecular β-Sheet Formation in α-Synuclein

DOI：10.1007/s10118-026-3674-x

摘要

Abstract

关键词

Keywords

references