Tetrabutylammonium based ionic liquids (ILs) inhibit the amyloid aggregation of superoxide dismutase 1 (SOD1)

Aggregation of a protein is associated with several biological and industrial processes: some wanted and some unwanted. An understanding of the mechanism of modulation of aggregation is, thus, required for designing strategies for the prevention/enhancement of amyloids. Misfolding and aggregation of human Cu-Zn superoxide dismutase (SOD1) into amyloid aggregates is a hallmark of a fatal neurodegenerative disease, amyotrophic lateral sclerosis (ALS). Therefore, targeting SOD1 protein could be a good choice for understanding the mechanism of SOD1 pathology in ALS. Here, we study the inhibitory effect of ammonium and choline based ionic liquids (ILs) (tetrabutylammonium methanesulfonate (TBAMS), tetrabutylammonium chloride (TBACl) and choline chloride (CholCl) on amyloid aggregation of SOD1 and explore how ILs modulate the formation of amyloid aggregates. We demonstrate that aqueous solutions of TBAMS and TBACl effectively inhibit SOD1 fibrillation, and their inhibitory effect increased with increasing the concentration. Conversely, CholCl has been found to act as an amyloid inhibitor at lower concentrations by acting at the elongation step and as an amyloid promoter at higher concentrations. Our experimental results showed that TBAMS and TBACl induce the formation of compact structures with reduced hydrophobicity. Theoretical analysis revealed that ILs stabilize Zn binding loop and electrostatic loop which play an important role in the structure and function of SOD1. These findings provide important insights about using IL as an anti-amyloidal agent for other amyloidogenic proteins and help to design effective modulators for protein aggregation. (c) 2022 Elsevier B.V. All rights reserved.

Automated summary

Protein aggregation plays a critical role in various biological and industrial processes. This study focuses on the inhibitory effect of ammonium and choline based ionic liquids (ILs) on the amyloid aggregation of human Cu-Zn superoxide dismutase (SOD1), a protein associated with amyotrophic lateral sclerosis (ALS). The results show that certain ILs effectively inhibit SOD1 fibrillation, while others have a dual effect of acting as an amyloid inhibitor at lower concentrations and a promoter at higher concentrations. The study also provides insights into the structural and functional role of ILs in stabilizing specific loop regions of SOD1.