Effect of α-Synuclein (1-17) Peptide for Cu2+-Bound and Metal-Free Forms by Molecular Dynamics Simulations

The Cu2+-bound and metal-free alpha-synuclein (1-17) peptides were simulated with the GROMOS 43A1 force field in the GROMACS package. There were six groups and each group was run for 500 ns in the physiological environment, giving a total of 3 mu s. It was found that the Cu2+-bound alpha-synuclein (1-17) peptide contained more unfluctuating secondary structure samples and more beta-conformations than the metal-free alpha-synuclein (1-17) peptide. Simulations indicate that the Cu2+-bound alpha-synuclein (1-17) peptide prefers conformations that allow larger solvent exposure of hydrophobic residues than the metal-free alpha-synuclein (1-17) peptide, which provides underlying evidence for why Cu2+ promotes the aggregation of alpha-synuclein. By mapping the free energy surface landscape, we found that conformations of Cu2+-bound alpha-synuclein (1-17) peptide distribute more compactly than the metal-free alpha-synuclein (1-17) peptide. The results are almost the same as the central conformation obtained by conformational clustering analysis. These new findings indicate that Cu2+ modulates the conformation of alpha-synuclein from intrinsic disorder to order, which is central to the conformational dynamic and thermodynamic properties of the Cu2+-bound and metal-free alpha-synuclein (1-17) peptides at the molecular level. This work is propitious to understanding the mechanisms of Cu2+ participation in the fibrillization of alpha-synuclein.