Histidine tautomerism dependent conformational transitions driven aggregation of profilin-1: Implications in amyotrophic lateral sclerosis

Aggregation of profilin-1 (PFN1) causes a fatal neurodegenerative disease, familial amyotrophic lateral sclerosis (fALS). Histidine (His) tautomerism has been linked to the formation of fibril aggregation causing neurodegenerative disease. Characterization of intermediate species that form during aggregation is crucial, however, this has proven very challenging for experimentalists due to their transient nature. Hence, molecular dynamics (MD) simulations have been performed on the His tautomeric isomers εε, εδ, δε, and δδ of PFN1 to explain the structural changes and to correlate them with its aggregation propensity. MD simulations show that His133 presumably plays a major role in the aggregation of PFN1 upon His tautomerism compared to His119. Further, the formation of a new 3