Residue-Specific Modulation of Aggregation-Associated Interactions by Spermine in Tau, α‑Synuclein, and Aβ40

TL;DR

This study shows how spermine affects the structure of three disease-related proteins, either promoting or preventing harmful clumping depending on specific protein regions.

Contribution

The paper reveals residue-specific effects of spermine on IDP aggregation, challenging the assumption that net charge alone determines its influence.

Findings

Spermine disrupts aggregation in Tau by binding near the fourth microtubule-binding repeat.

Spermine enhances α-synuclein aggregation by redistributing contacts in the C-terminal region.

Spermine promotes Aβ40 fibril formation by neutralizing acidic residues near position 22–24.

Abstract

Preventing neurodegenerative diseases associated with
intrinsically
disordered proteins (IDPs) remains a major challenge due to the lack
of a detailed, sequence-level picture of disease-relevant structure
formation and the influence of cellular factors that modulate these
transitions. Here, we probe spermine (Spm), a +4 charged polyamine
abundant in cells, to determine how it reshapes the conformational
ensembles and fibril-associated contact propensities of three disease-linked
IDPs: the K18 domain of Tau, α-synuclein (αS), and amyloid-β40
(Aβ40). Using long all-atom molecular dynamics simulations across
a range of Spm concentrations, we quantify residue-level changes in
intrachain contacts relative to native contacts observed in fibrils
and corroborate computational predictions with ThT fluorescence assays
for Tau constructs. Spm acts in a sequence- and region-specific manner,
not simply through the overall net charge. In K18, Spm binds near
the fourth microtubule-binding repeat, disrupting intrachain contacts
associated with Alzheimer’s fibril structures and thereby inhibiting
aggregation. In αS, Spm binds mainly to acidic residues in the
C-terminal half of the sequence and redistributes intramolecular contacts
to enhance aggregation-prone interactions in the central region, providing
a residue-level mechanistic basis for previously reported Spm-enhanced
αS aggregation. For Aβ40, Spm neutralizes acidic residues
near positions 22–24 and shifts intrachain interactions toward
its aggregation-prone core, resulting in a net promotion of fibril-like
conformations. These divergent effects show that net charge alone
cannot predict the polyamine influence on IDPs. Instead, residue-specific
binding hotspots and local reweighting of aggregation-linked contacts
determine whether Spm promotes or suppresses fibril-like conformations.
This combined simulation–experimental framework provides a
mechanistic basis for how small molecules reprogram IDP conformational
ensembles and suggests principles for designing ligands that exploit
similar residue-level modulation.

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