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

doi:10.3866/PKU.WHXB201111231

摘要/Abstract

摘要： 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500 ns, 总模拟时间为3 μs. 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.

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

MSC2000:

O641

曹剑, 曹赞霞, 赵立岭, 王吉华. 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[J]. 物理化学学报, 2012, 28(02): 479-488.

CAO Jian, CAO Zan-Xia, ZHAO Li-Ling, WANG Ji-Hua. Effect of α-Synuclein (1-17) Peptide for Cu²⁺-Bound and Metal-Free Forms by Molecular Dynamics Simulations[J]. Acta Phys. -Chim. Sin., 2012, 28(02): 479-488.

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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 Cu²⁺-Bound and Metal-Free Forms by Molecular Dynamics Simulations

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