@article {Nair26a,
	author = {Nair, Radhika V and Tran, Bich Ngoc and Parikh, Atul N and Foreman, Matthew R},
	title = {Small molecule ensembles reshape amyloid aggregation landscapes},
	elocation-id = {2026.02.22.706957},
	year = {2026},
	doi = {10.64898/2026.02.22.706957},
	publisher = {Cold Spring Harbor Laboratory},
	abstract = {Amyloid-β42 (Aβ42) assemblies form a dynamic network of oligomers and fibrils, with fibrillar species acting as reservoirs that maintain equilibrium among intermediates. Perturbing a single species shifts the oligomer-fibril balance, highlighting the challenge of selectively targeting toxic species while maintaining the dynamic equilibrium of the amyloid network. Here, we show that the small molecule EPPS (4-(2-hydroxyethyl)-1-piperazine-propanesulfonic acid) fine-tunes this network through cooperative, concentration-dependent disaggregation. At optimal concentrations, EPPS efficiently shifts the equilibrium away from the fibrillar structures via multisite, allosteric interactions. At higher concentrations, EPPS self-assembles into supramolecular clusters, depleting free molecules and allowing partially disaggregated amyloid intermediates to reassemble. Notably, at elevated concentrations, interactions transition from molecule-to-molecule to higher-order ensemble-to-ensemble engagement, where EPPS clusters and amyloid fibrils mutually reshape each other{\textquoteright}s dynamics. Molecular crowding, modeled with polyethylene glycol, further restricts EPPS access to fibrillar surfaces, modulating activity. These findings reveal that small-molecule dynamics-including cooperative binding, self-assembly, and environment-dependent accessibility-critically govern amyloid network control, providing a mechanistic blueprint for rational design of next-generation amyloid-targeting therapeutics.Competing Interest StatementThe authors have declared no competing interest.Ministry of Education, Singapore, EDUNC-33-18-279-V12},
	URL = {https://www.biorxiv.org/content/early/2026/02/23/2026.02.22.706957},
	eprint = {https://www.biorxiv.org/content/early/2026/02/23/2026.02.22.706957.full.pdf},
	journal = {bioRxiv}
}