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<p>Interactions between the intrinsically disordered protein <i>α</i>-synuclein (<i>α</i>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 <i>α</i>S chain. While AT-rich sequences engage <i>α</i>S yet induce DNA duplex destabilization with minimal protein structuring, GC-rich tracts promote localized protein compaction and secondary <i>β</i>-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 <i>β</i>-sheet within the N-terminal and nonamyloid component regions of the <i>α</i>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, dominating 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 <i>α</i>S folding, with potential implications for its aggregation propensity and regulatory functions in gene expression.</p>

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

  • 期刊论文

  • 发表日期：

    2026年5月30日

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  • Yi-Heng Zhang,
  • Shuai Gong,
  • Yu Yuan,
  • Lei Shen

摘要

Interactions between the intrinsically disordered protein α-synuclein (αS) 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 αS chain. While AT-rich sequences engage αS yet induce DNA duplex destabilization with minimal protein structuring, GC-rich tracts promote localized protein compaction and secondary β-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 β-sheet within the N-terminal and nonamyloid component regions of the αS 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, dominating 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 αS folding, with potential implications for its aggregation propensity and regulatory functions in gene expression.