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.

参考文献

(1) Singleton, A. B.; Farrer, M.; Johnson, J.; Singleton, A.; Hague, S.; Kachergus, J.; Hulihan, M.; Peuralinna, T.; Dutra, A.; Nussbaum, R.; Lincoln, S.; Crawley, A.; Hanson, M.; Maraganore, D.; Adler, C.; Cookson, M. R.; Muenter, M.; Baptista, M.; Miller, D.; Blancato, J.; Hardy, J.; Gwinn-Hardy, K. Science 2003, 302 (5646), 841.
(2) Kruger, R.; Kuhn,W.; Muller, T.;Woitalla, D.; Graeber, M.; Kosel, S.; Przuntek, H.; Epplen, J. T.; Schols, L.; Riess, O. Nat. Genet. 1998, 18 (2), 106.
(3) Volles, M. J.; Lansbury, P. T. Jr. Biochemistry 2003, 42 (26), 7871.
(4) Zarranz, J. J.; Alegre, J.; Gomez-Esteban, J. C.; Lezcano, E.; Ros, R.; Ampuero, I.; Vidal, L.; Hoenicka, J.; Rodriguez, O.; Atares, B.; Llorens, V.; Gomez-Tortosa, E.; del Ser, T.; Munoz, D. G.; de Yebenes, J. G. Ann. Neurol. 2004, 55 (2), 164.
(5) Giasson, B. I.; Murray, I. V.; Trojanowski, J. Q.; Lee, V. M. J. Biol. Chem. 2001, 276 (4), 2380.
(6) Bodner, C. R.; Maltsev, A. S.; Dobson, C. M.; Bax, A. Biochemistry 2010, 49 (5), 862.
(7) Hoyer,W.; Cherny, D.; Subramaniam, V.; Jovin, T. M. M. Biochemistry 2004, 43 (51), 16233.
(8) Dunker, A. K.; Brown, C. J.; Lawson, J. D.; Iakoucheva, L. M.; Obradovic, Z. Biochemistry 2002, 41 (21), 6573.
(9) Huang,Y. Q.; Liu, Z. R. Acta Phys. -Chim. Sin. 2010, 26 (8), 2061. [黄永棋, 刘志荣. 物理化学学报, 2010, 26 (8), 2061.]
(10) Bertoncini, C.W.; Jung, Y. S.; Fernandez, C. O.; Hoyer,W.; Griesinger, C.; Jovin, T. M.; Zweckstetter, M. Proc. Natl. Acad. Sci. U S A 2005, 102 (5), 1430.
(11) Dedmon, M. M.; Lindorff-Larsen, K.; Christodoulou, J.; Vendruscolo, M.; Dobson, C. M. J. Am. Chem. Soc. 2005, 127 (2), 476.
(12) Spillantini, M. G.; Crowther, R. A.; Jakes, R.; Hasegawa, M.; Goedert, M. Proc. Natl. Acad. Sci. U S A 1998, 95 (11), 6469.
(13) Masliah, E.; Rockenstein, E.; Veinbergs, I.; Mallory, M.; Hashimoto, M.; Takeda, A.; Sagara, Y.; Sisk, A.; Mucke, L. Science 2000, 287 (5456), 1265.
(14) Allsop, D.; Mayes, J.; Moore, S.; Masad, A.; Tabner, B. J Biochem. Soc. Trans. 2008, 36, 1293.

(15) Paik, S. R.; Shin, H. J.; Lee, J. H.; Chang, C. S.; Kim, J. Biochem. J. 1999, 340, 821.

(16) Davies, P.;Wang, X.; Sarell, C. J.; Drewett, A.; Marken, F.; Viles, J. H.; Brown, D. R. Biochemistry 2010, 50 (1), 37.
(17) Gorell, J. M.; Johnson, C. C.; Rybicki, B. A.; Peterson, E. L.; Kortsha, G. X.; Brown, G. G.; Richardson, R. J. Neurotoxicology 1999, 20, 239.
(18) Pall, H. S.;Williams, A. C.; Blake, D. R.; Lunec, J.; Gutteridge, J. M.; Hall, M.; Taylor, A. Lancet 1987, 2, 238.
(19) Rasia, R. M.; Bertoncini, C.W.; Marsh, D.; Hoyer,W.; Cherny, D.; Zweckstetter, M.; Griesinger, C.; Jovin, T. M.; Fernandez, C. O. Proc. Natl. Acad. Sci. U S A 2005, 102 (12), 4294.
(20) Binolfi, A.; Lamberto, G. R.; Duran, R.; Quintanar, L.; Bertoncini, C.W.; Souza, J. M.; Cervenansky, C.; Zweckstetter, M.; Griesinger, C.; Fernandez, C. O. J. Am. Chem. Soc. 2008, 130 (35), 11801.
(21) Jackson, M. S.; Lee, J. C. Inorg. Chem. 2009, 48 (19), 9303.
(22) Luk, K. C.; Mills, I. P.; Trojanowski, J. Q.; Lee, V. M. Biochemistry 2008, 47 (47), 12614.
(23) Drew, S. C.; Leong, S. L.; Pham, C. L.; Tew, D. J.; Masters, C. L.; Miles, L. A.; Cappai, R.; Barnham, K. J. Am. Chem. Soc. 2008, 130 (24), 7766.
(24) Wang, J. H.; Cao, Z. X.; Li, S. Q. Curr. Comput. -Aided Drug Des. 2009, 5 (4), 280.
(25) Sung, Y. H.; Rospigliosi, C.; Eliezer, D. Biochim. Biophys Acta 2006, 1764 (1), 5.
(26) Kowalik-Jankowska, T.; Rajewska, A.; Jankowska, E.; Grzonka, Z. Dalton Trans. 2006, 42, 5068.
(27) McCammon, J. A.; Gelin, B. R.; Karplus, M. Nature 1977, 267 (5612), 585.
(28) Daggett, V.; Kollman, P. A.; Kuntz, I. D. Biopolymers 1991, 31 (3), 285.
(29) Karplus, M.; Petsko, G. A. Nature 1990, 347 (6294), 631.
(30) Tsigelny, I. F.; Bar-On, P.; Sharikov, Y.; Crews, L.; Hashimoto, M.; Miller, M. A.; Keller, S. H.; Platoshyn, O.; Yuan, J. X.; Masliah, E. Federation of European Biochemical Societies Journal 2007, 274 (7), 1862.
(31) Riihimaki, E. S.; Martinez, J. M.; Kloo, L. J. Phys. Chem. B 2007, 111 (35), 10529.
(32) Cao, Z. X.; Liu, L.;Wang, J. H. J. Biomol. Struct. Dyn. 2010, 28 (3), 343.
(33) Kowalik-Jankowska, T.; Rajewska, A.;Wisniewska, K.; Grzonka, Z.; Jezierska, J. J. Inorg. Biochem. 2005, 99 (12), 2282.
(34) Ulmer, T. S.; Bax, A.; Cole, N. B.; Nussbaum, R. L. J. Biol. Chem. 2005, 280 (10), 9595.
(35) Binolfi, A.; Rodriguez, E. E.; Valensin, D.; D'Amelio, N.; Ippoliti, E.; Obal, G.; Duran, R.; Magistrato, A.; Pritsch, O.; Zweckstetter, M.; Valensin, G.; Carloni, P.; Quintanar, L.; Griesinger, C.; Fernandez, C. O. Inorg. Chem. 2010, 49 (22), 10668.
(36) van der Spoel, D.; van Drunen, R.; Berendsen, H. J. C. Groningen Machine for Chemical Simulations, Department of Biophysical Chemistry, BIOSON Research Institute: Nijenborgh 4 NL-9717 AG Groningen, 1994.
(37) Daura, X.; Mark, A. E.; van Gunsteren,W. F. J. Comput. Chem. 1998, 19 (5), 535.
(38) van Gunsteren,W. F.; Billeter, S. R.; Eising, A. A.; Hunenberger, P. H.; Krüger, P.; Mark, A. E.; Scott,W. R. P.; Tironi, I. G. Eds. Biomolecular Simulation: The GROMOS96 Manual and User Guide; Zürich, Switzerland: Hochschulverlag AG an der ETH Zürich. 1996.
(39) Berendsen, H. J. C.; Postma, J. P. M.; van Gunsteren,W. F.; Hermans, J. Intermolecular Forces; Pullman, B. Ed.; Reidel: Dordrecht, 1981; p331.
(40) Tironi, I. G.; Sperb, R.; Smith, P. E.; van Gunsteren,W. F. J. Chem. Phys. 1995, 102 (13), 5451.
(41) Smith, P. E.; van Gunsteren,W. F. J. Chem. Phys. 1994, 100 (4), 3169.
(42) Berendsen, H. J. C.; Postma, J. P. M.; van Gunsteren,W. F.; Dinola, A.; Haak, J. R. J. Chem. Phys. 1984, 81 (8), 3684.
(43) Ryckaert, J. P.; Ciccotti, G.; Berendsen, H. J. C. J. Comput. Phys. 1977, 23 (3), 327.
(44) Hu, H.; Elstner, M.; Hermans, J. Proteins 2003, 50 (3), 451.
(45) Frishman, D.; Argos, P. Proteins 1995, 23 (4), 566.
(46) Heinig, M.; Frishman, D. Nucleic Acids Res. 2004, 32,W500.
(47) Apetri, M. M.; Maiti, N. C.; Zagorski, M. G.; Carey, P. R.; Anderson, V. E. J. Mol. Biol. 2006, 355 (1), 63.
(48) Heise, H.; Hoyer,W.; Becker, S.; Andronesi, O. C.; Riedel, D.; Baldus, M. Proc. Natl. Acad Sci. U S A, 2005, 102 (44), 15871.
(49) Maiti, N. C.; Apetri, M. M.; Zagorski, M. G.; Carey, P. R.; Anderson, V. E. J. Am. Chem. Soc. 2004, 126 (8), 2399.
(50) Croke, R. L.; Sallum, C. O.;Watson, E.;Watt, E. D.; Alexandrescu, A. T. Protein Sci. 2008, 17 (8), 1434.
(51) Waxman, E. A.; Mazzulli, J. R.; Giasson, B. I. Biochemistry 2009, 48 (40), 9427.
(52) Pronchik, J.; He, X.; Giurleo, J. T.; Talaga, D. S. J. Am. Chem. Soc. 2010, 132 (28), 9797.
(53) Wang, X.; Moualla, D.;Wright, J. A.; Brown, D. R. J. Neurochem. 2010, 113 (3), 704.

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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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