关键词: 动力学模拟, Cu²⁺-α-突触核蛋白, 二级结构, 自由能, 纤维化聚集

Abstract: The Cu²⁺-bound and metal-free α-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 μs. It was found that the Cu²⁺-bound α-synuclein (1-17) peptide contained more unfluctuating secondary structure samples and more ^β-conformations than the metal-free α-synuclein (1-17) peptide. Simulations indicate that the Cu²⁺-bound α-synuclein (1-17) peptide prefers conformations that allow larger solvent exposure of hydrophobic residues than the metal-free α-synuclein (1-17) peptide, which provides underlying evidence for why Cu²⁺ promotes the aggregation of α-synuclein. By mapping the free energy surface landscape, we found that conformations of Cu²⁺-bound α-synuclein (1-17) peptide distribute more compactly than the metal-free α-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 α-synuclein from intrinsic disorder to order, which is central to the conformational dynamic and thermodynamic properties of the Cu²⁺-bound and metal-free α-synuclein (1-17) peptides at the molecular level. This work is propitious to understanding the mechanisms of Cu²⁺ participation in the fibrillization of α-synuclein.

Key words: Molecular dynamics simulations, Cu²⁺-α-synuclein, Secondary structure, Free energy, Fibrotic aggregation