Regulation of Protein Disaggregation and its Cytotoxicity by the Hydrophobic Chain Length of Ammonium-Based Ionic Liquids

Abstract

Amyloid formation and protein aggregation are essential mechanisms in a number of physiologic and pathological circumstances. This study explores the influence of ammonium-based ionic liquids with varying hydrophobic alkyl chain lengths (N2, N4, N6, and N8) on the aggregation and disaggregation of Bone Morphogenetic Protein-2 (BMP-2). Heat-induced aggregation led to a substantial increase in hydrodynamic radius, with measurements revealing an increase from 12 ± 5 nm (native BMP-2) to 400 ± 30 nm. Treatment with N8 further increased the aggregate size to 635 ± 43 nm, supporting the formation of mature fibrils. Conversely, shorter-chain ionic liquids (N2 and N4) reduced the aggregate size significantly to 42 ± 5 nm and 37 ± 11 nm, respectively, indicating effective disaggregation. Spectroscopic analysis confirmed enhanced β-sheet content in fibrillar structures, particularly in N8-treated samples, while FTIR and microscopy revealed structural differences across treatments. Cytotoxicity assays demonstrated that fibrillar aggregates exhibited higher oxidative stress and cell damage, whereas disaggregated structures formed by shorter-chain ionic liquids showed reduced toxicity. These findings underscore the potential of ionic liquids in modulating protein aggregation pathways, offering valuable insights for amyloid research and therapeutic strategies.

Supplementary files

Article information

Article type
Paper
Submitted
03 Apr 2025
Accepted
11 Jul 2025
First published
11 Jul 2025

Phys. Chem. Chem. Phys., 2025, Accepted Manuscript

Regulation of Protein Disaggregation and its Cytotoxicity by the Hydrophobic Chain Length of Ammonium-Based Ionic Liquids

D. P. Behera, P. R. Hota, K. Dash, M. Mishra and H. Sahoo, Phys. Chem. Chem. Phys., 2025, Accepted Manuscript , DOI: 10.1039/D5CP01280E

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