分子动力学模拟Cu2＋对α-突触核蛋白(1-17)肽段构象变化的影响

Effect of α-Synuclein(1-17) Peptide for Cu～(2+)-Bound and Metal-Free Forms by Molecular Dynamics Simulations

利用分子动力学模拟研究铜离子(Cu2+)对α-突触核蛋白1-17号氨基酸肽段(α-synuclein(1-17))构象变化的影响,采用GROMOS 43A1力场对Cu2+-α-synuclein(1-17)复合体和α-synuclein(1-17)肽段单体分别进行了6组独立的分子动力学模拟,每组模拟时间为500ns,总模拟时间为3μs.研究结果表明:Cu2+与α-synuclein(1-17)肽段结合使其更易向β折叠片结构折叠,促进了其二级结构的形成,增强了构象的稳定性;Cu2+增大了α-synuclein肽段疏水残基的溶剂可及表面积,增强了其疏水残基的暴露程度.自由能分析指出,Cu2+-α-synuclein(1-17)复合体的自由能比α-synuclein(1-17)肽段低,构象稳定,采样空间紧密,其自由能极小构象为β折叠片结构.构象聚类分析进一步表明,Cu2+使得α-synuclein(1-17)肽段构象趋于稳定.总之,Cu2+诱导固有无序蛋白α-synuclein(1-17)肽段由无序向有序转变,降低了构象的自由能,同时Cu2+增强了α-synuclein(1-17)肽段的疏水性,使得α-synuclein肽段因疏水作用更倾向于形成β折叠片结构,加速其疏水性聚集.

The Cu2＋-bound and metal-free msynuclein （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 ps. 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 msynuclein （1-17） peptide, which provides underlying evidence for why Cu2＋ promotes the aggregation of a-synuclein. By mapping the free energy surface landscape, we found that conformations of Cu2＋-bound a-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.