Computational Modeling of the Effect of Trifluoroethanol on the Conformation of α-Synuclein Peptide

Alpha-Synuclein is a presynaptic neuronal protein whose masses are involved in Parkinson’s disease, a chronic and progressive neurodegenerative disorder of the central nervous system. It has been observed that upon exposure to anionic surfactants, fluorinated alcohols and membranes in vitro, [Formula: see text]-synuclein adopts alpha helix structure and can be fibrillated, while in aqueous solution, the protein is intrinsically disordered and the fibrillation is undesirable. Solvent is one of the most critical environmental parameters in biological studies as well as computer simulations. In this paper, we have investigated the effect of solvent composition on the conformation of [Formula: see text]-synuclein protein using molecular dynamics (MD) simulations. For this purpose, the effect of different combinations of water and trifluoroethanol (TFE) solvents on the secondary structure of a fragment of [Formula: see text]-synuclein was investigated. Moreover, thermodynamic calculations were performed through a coarse-grained (CG) model of solutions with different concentrations of [Formula: see text]-synuclein in the aqueous phase and in TFE medium. The potential of mean force (PMF) calculations was performed as a function of separation distance between the centers of masses of two peptides. The results indicated that in the presence of TFE, the secondary structures have a regular arrangement of amino acids stabilized by hydrogen bonding patterns. In addition, decreasing the TFE concentration reduces the stability of [Formula: see text]-helix structures of the protein. It seems that in diluted TFE solutions, high concentrations of water in the medium lead to the breakage of peptide–TFE hydrogen bonds. However, the hydrophobic nature of TFE and [Formula: see text]-synuclein molecules prevents further aggregation in the concentrated solutions.