物理化学学报 >> 2012, Vol. 28 >> Issue (02): 479-488.doi: 10.3866/PKU.WHXB201111231

生物物理化学 上一篇    下一篇

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

曹剑1,2, 曹赞霞1, 赵立岭1, 王吉华1   

  1. 1. 德州学院, 山东省功能大分子生物物理重点实验室, 山东德州 253023;
    2. 山东师范大学物理与电子科学学院, 济南 250014
  • 收稿日期:2011-09-19 修回日期:2011-11-09 发布日期:2012-01-11
  • 通讯作者: 王吉华 E-mail:jhwyh@yahoo.com.cn
  • 基金资助:

    国家自然科学基金(30970561, 31000324)资助项目

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

CAO Jian1,2, CAO Zan-Xia1, ZHAO Li-Ling1, WANG Ji-Hua1   

  1. 1. Shandong Provincial Key Laboratory of Functional Macromolecular Biophysics, Dezhou University, Dezhou 253023, Shandong Province, P. R. China;
    2. College of Physics and Electronics Science, Shandong Normal University, Jinan 250014, P. R. China
  • Received:2011-09-19 Revised:2011-11-09 Published:2012-01-11
  • Contact: WANG Ji-Hua E-mail:jhwyh@yahoo.com.cn
  • Supported by:

    The project was supported by the National Natural Science Foundation of China (30970561, 31000324).

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+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