Effect of Osmolytes on Conformational Behavior of Intrinsically Disordered Protein α-Synuclein

alpha-Synuclein is an intrinsically disordered protein whose function in a healthy brain is poorly understood. It is genetically and neuropathologically linked to Parkinson's disease (PD). PD is manifested after the accumulation of plaques of alpha-synuclein aggregates in the brain cells. Aggregates of alpha-synuclein are very toxic and lead to the disruption of cellular homeostasis and neuronal death. alpha-Synuclein can also contribute to disease propagation as it may exert noxious effects on neighboring cells. Understanding the mechanism of alpha-synuclein aggregation will facilitate the problem of dealing with neurodegenerative diseases in general and that of PD in particular. Here, we have used molecular dynamics simulations to investigate the behavior of alpha-synuclein at various temperatures and in different concentrations of urea and trimethyl amine oxide. The residue region from 61 to 95 of alpha-synuclein is experimentally known as amyloidogenic. In our study, we have identified some other regions, which also have the propensity to form an aggregate besides this known sequence. Urea being a denaturant interacts more with these regions of alpha-synuclein through hydrogen bond formation and inhibits the beta-sheet formation, whereas trimethyl amine oxide itself does not interact much with the protein and stabilizes the protein by preferentially distributing water molecules on the surface of the protein.