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姓名	李健賓(Jian-Bin Lee)  查詢紙本館藏	畢業系所	化學學系
論文名稱	(A Replica-Exchange Molecular Dynamics Study of the Configurations of Alzheimer Amyloid beta-Peptide within Membrane: Implications for Aggregation and Toxicity)
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摘要(中)	Amyloid-beta(Abeta)胜肽在腦中聚集形成類澱粉斑塊沉澱，堆積在神經細胞膜上造成神經細胞死亡，是阿茲海默症的主要特徵。Abeta胜肽的生成，是由類澱粉前驅蛋白被細胞膜上的beta和γ酵素切割後所生成的片段。因為Abeta的生成在含有生物膜的環境，所以我們對於Abeta胜肽在生物膜上的位置及結構有很大的興趣，也希望能更進一步得到Abeta在生物膜上的聚集機制與神經毒性的洞見。我們使用平行淬煉分子動態法搭配電場膜的模型，進行Abeta(25-35) 胺基酸突變及序列交換的研究和全長Abeta(1-40)以及家族性遺傳變異體E22Q-Abeta(1-40)、D23N-Abeta(1-40)、 E22Q/D23N-Abeta(1-40)的研究。我們根據Abeta(25-35)模擬的結果，有效的得知Abeta(25-35)及其衍生物，在膜環境中的組態與毒性之間的相關性，我們在完成此研究之後，補充了先前無法透過輸水性與毒性的關聯解釋的實驗結果。接下來進一步研究全長的Abeta(1-40)以及家族性遺傳變異體，相較於阿茲海默症，有些早發型阿茲海默症被稱為家族性阿茲海默症，具遺傳性的家族性阿茲海默症源自於基因的突變，早發型阿茲海默症的患者中，發現類澱粉蛋白的聚集量增加。從相關的文獻搜尋中，目前尚未有系統性的研究，關於家族性突變Abeta胜肽在生物膜的環境當中的分子動態模擬研究。根據我們模擬的結果顯示，家族性突變體與Abeta相比，N端的胺基酸與中心疏水核心之間的網絡連結有減少的趨勢。此外我們也觀察到了家族性突變體，中心疏水核心組態的轉變，較容易從低暴露在水中的組態，轉換成無結構並高暴露在水中的組態，從這樣的結果，我們推論較無結構且暴露在水中的中心疏水核心，可以加速家族性突變的Aβ的聚集過程。本研究合理解釋了家族性阿茲海默症的Aβ為何能快速的聚集，且從藥物設計的角度上，提供藥物設計的方向，設計合理的藥物及療法。
摘要(英)	Extracellular deposits of amyloidbeta (Abeta) aggregates in brain is the hallmark of Alzheimer’s disease (AD). Abeta peptide is produced from the amyloid precursor protein (APP) within membrane by the proteolytic action of thebeta- and γ-secretases. Therefore, it is crucial to determine the configuration of Abeta peptide within a membrane to provide insights at atomic levels for the aggregation mechanism and toxicity. In this thesis, we employed replica-exchange molecular dynamics in conjunction with an implicit membrane model to investigate the mutation and sequence effects of short Abeta(25-35) fragment and familial mutations (E22Q (Dutch), D23N (Iowa) and E22Q/D23N (Dutch/Iowa) mutants) of full length Abeta(1–40) peptide on their configurations within a membrane. Our work on Abeta(25-35) and its mutants correlated the configurations of peptides within membrane with their toxicities complementing the hydrophobicity-toxicity relationship. In the work of familial mutations of Abeta, we find that the central hydrophobic core (CHC) (residues 17-21) of familial mutants is less protected and thus more exposed to the solvent than that of Abeta(1–40) peptide due to their weal long-range contacts with the N-terminal (residues 1-16). Moreover, for the familial mutants, their energy barriers for the inter-conversion of the CHC configurations between membrane and water phases is lower than that of Abeta(1–40). Therefore, it is faster for the familial mutants to convert their CHCs from membrane (less surface-exposed) to water phase (highly surface-exposed), when their CHC populations in the water phase are decreased (e.g. aggregated). As the amyloid fibril is deposited on membrane, these findings are helpful to understand the experimental observations that the familial Abeta peptides aggregate much faster than that of Abeta(1–40). This study provides the insight for the rational drug design to prevent amyloid associated diseases.
關鍵字(中)	★ 類澱粉蛋白質 ★ 胜肽 ★ 阿茲海默症 ★ 家族性阿茲海默症 ★ 組態 ★ 分子動態模擬	關鍵字(英)	★ Amyloid beta peptide ★ peptides ★ Alzheimer’s disease ★ Familial Alzheimer’s disease ★ Configuration ★ Molecular Dynamic Simulation
論文目次	中文摘要..........i Abstract.........iii 致謝..............v Notation Illustration............xi Chapter 1- Introduction...........1 Chapter 2- Methods................14 I. The configuration of familial mutants of full-length Aβ within membrane..........14 II. Aβ(25-35) mutation effect within membrane.....20 III. Aβ(25-35) sequence effect within membrane....21 Chapter 3- Results and Discussion....................24 I. The configuration of familial mutants of full-length Aβ within membrane...............24 Secondary Structure....................24 Location of A(1-40) Peptide and Mutants within the Membrane..................35 Tertiary Structure............42 Free Energy Landscapes...............51 II. Aβ(25-35) mutation effect within membrane.....71 Location of peptide residues in the membrane.........71 Peptide conformations in a water-membrane environment.... 80 Orientation of peptide inserting into the membrane.....88 Implications for aggregation and neurotoxicity.........95 III. Aβ(25-35) sequence effect within membrane.....100 Energy Landscape of Peptide Folding and Membrane Insertion...........100 Location of Peptide within the Membrane.........107 Unpaired H-Bonding Sites of Peptides............114 Neurotoxicity of Peptides...............116 Chapter 4- Conclusion...................123 Reference...............................127 Appendix A..............................143 Appendix B..............................149 Publications............................149 Manuscript in Preparation...............150
參考文獻	[1] B.A. Christian, The formation and stabilization of protein structure, Biochem. J., 128 (1972) 737-749. [2] M. Stefani, C. Dobson, Protein aggregation and aggregate toxicity: new insights into protein folding, misfolding diseases and biological evolution, J. Mol. Med., 81 (2003) 678-699. [3] C.M. Dobson, Protein Folding and Disease: a view from the first Horizon Symposium, Nat. Rev. Drug Discov., 2 (2003) 154-160. [4] J.-C. Rochet, P.T. Lansbury Jr, Amyloid fibrillogenesis: themes and variations, Curr. Opin. Struct. Biol., 10 (2000) 60-68. [5] R. Jakob-Roetne, H. Jacobsen, Alzheimer′s Disease: From Pathology to Therapeutic Approaches, Angew. Chem. Int. Edit., 48 (2009) 3030-3059. [6] J. Hardy, D.J. Selkoe, The amyloid hypothesis of Alzheimer′s disease: Progress and problems on the road to therapeutics, Science, 297 (2002) 353-356. [7] R. Kayed, E. Head, J.L. Thompson, T.M. McIntire, S.C. Milton, C.W. Cotman, C.G. Glabe, Common structure of soluble amyloid oligomers implies common mechanism of pathogenesis, Science, 300 (2003) 486-489. [8] C. Haass, D.J. Selkoe, Soluble protein oligomers in neurodegeneration: lessons from the Alzheimer′s amyloid [beta]-peptide, Nat. Rev. Mol. Cell Biol., 8 (2007) 101-112. [9] R. Vassar, M. Citron, A[beta]-Generating Enzymes: Recent Advances in [beta]- and [gamma]-Secretase Research, Neuron, 27 (2000) 419-422. [10] G. Bitan, M.D. Kirkitadze, A. Lomakin, S.S. Vollers, G.B. Benedek, D.B. Teplow, Amyloid β-protein (Aβ) assembly: Aβ40 and Aβ42 oligomerize through distinct pathways, Proc. Natl. Acad. Sci. U S A, 100 (2003) 330-335. [11] G. Meisl, X. Yang, E. Hellstrand, B. Frohm, J.B. Kirkegaard, S.I.A. Cohen, C.M. Dobson, S. Linse, T.P.J. Knowles, Differences in nucleation behavior underlie the contrasting aggregation kinetics of the A beta 40 and A beta 42 peptides, Proc. Natl. Acad. Sci. U S A, 111 (2014) 9384-9389. [12] C.J. Barrow, A. Yasuda, P.T.M. Kenny, M.G. Zagorski, Solution conformations and aggregational properties of synthetic amyloid β-peptides of Alzheimer′s disease, J. Mol. Biol., 225 (1992) 1075-1093. [13] D.M. Walsh, I. Klyubin, J.V. Fadeeva, W.K. Cullen, R. Anwyl, M.S. Wolfe, M.J. Rowan, D.J. Selkoe, Naturally secreted oligomers of amyloid beta protein potently inhibit hippocampal long-term potentiation in vivo, Nature, 416 (2002) 535-539. [14] D.M. Hartley, D.M. Walsh, C.P.P. Ye, T. Diehl, S. Vasquez, P.M. Vassilev, D.B. Teplow, D.J. Selkoe, Protofibrillar intermediates of amyloid beta-protein induce acute electrophysiological changes and progressive neurotoxicity in cortical neurons, J. Neurosci., 19 (1999) 8876-8884. [15] M.P. Lambert, A.K. Barlow, B.A. Chromy, C. Edwards, R. Freed, M. Liosatos, T.E. Morgan, I. Rozovsky, B. Trommer, K.L. Viola, P. Wals, C. Zhang, C.E. Finch, G.A. Krafft, W.L. Klein, Diffusible, nonfibrillar ligands derived from A beta(1-42) are potent central nervous system neurotoxins, Proc. Natl. Acad. Sci. U. S. A., 95 (1998) 6448-6453. [16] O. Crescenzi, S. Tomaselli, R. Guerrini, S. Salvadori, A.M. D′Ursi, P.A. Temussi, D. Picone, Solution structure of the Alzheimer amyloid β-peptide (1–42) in an apolar microenvironment, Eur. J. Biochem., 269 (2002) 5642-5648. [17] H. Sticht, P. Bayer, D. Willbold, S. Dames, C. Hilbich, K. Beyreuther, R.W. Frank, P. Rösch, Structure of Amyloid A4-(1–40)-Peptide of Alzheimer′s Disease, Eur. J. Biochem., 233 (1995) 293-298. [18] M. Coles, W. Bicknell, A.A. Watson, D.P. Fairlie, D.J. Craik, Solution Structure of Amyloid β-Peptide(1−40) in a Water−Micelle Environment. Is the Membrane-Spanning Domain Where We Think It Is?, Biochemistry, 37 (1998) 11064-11077. [19] R. Tycko, K.L. Sciarretta, J.P.R.O. Orgel, S.C. Meredith, Evidence for Novel β-Sheet Structures in Iowa Mutant β-Amyloid Fibrils, Biochemistry, 48 (2009) 6072-6084. [20] Z. Martinez, M. Zhu, S. Han, A.L. Fink, GM1 Specifically Interacts with α-Synuclein and Inhibits Fibrillation, Biochemistry, 46 (2007) 1868-1877. [21] M. Zhu, A.L. Fink, Lipid Binding Inhibits α-Synuclein Fibril Formation, J. Biol. Chem., 278 (2003) 16873-16877. [22] N. Carulla, G.L. Caddy, D.R. Hall, J. Zurdo, M. Gairi, M. Feliz, E. Giralt, C.V. Robinson, C.M. Dobson, Molecular recycling within amyloid fibrils, Nature, 436 (2005) 554-558. [23] B. O′Nuallain, S. Shivaprasad, I. Kheterpal, R. Wetzel, Thermodynamics of Aβ(1−40) Amyloid Fibril Elongation, Biochemistry, 44 (2005) 12709-12718. [24] E. Ambroggio, Surface Behavior and Lipid Interaction of Alzheimer β-Amyloid Peptide 1–42: A Membrane-Disrupting Peptide, Biophys. J., 88 (2005) 2706-2713. [25] H.-J. Lee, C. Choi, S.-J. Lee, Membrane-bound α-Synuclein Has a High Aggregation Propensity and the Ability to Seed the Aggregation of the Cytosolic Form, J. Biol. Chem., 277 (2002) 671-678. [26] N.B. Cole, D.D. Murphy, T. Grider, S. Rueter, D. Brasaemle, R.L. Nussbaum, Lipid Droplet Binding and Oligomerization Properties of the Parkinson′s Disease Protein α-Synuclein, J. Biol. Chem., 277 (2002) 6344-6352. [27] S. Askarova, X. Yang, J.C.M. Lee, Impacts of Membrane Biophysics in Alzheimer′s Disease: From Amyloid Precursor Protein Processing to Aβ Peptide-Induced Membrane Changes, International Journal of Alzheimer′s Disease, 2011 (2011) 1-12. [28] S.M. Butterfield, H.A. Lashuel, Amyloidogenic Protein-Membrane Interactions: Mechanistic Insight from Model Systems, Angew. Chem. Int. Ed, 49 (2010) 5628-5654. [29] M.M. Ouberai, J. Wang, M.J. Swann, C. Galvagnion, T. Guilliams, C.M. Dobson, M.E. Welland, alpha-Synuclein Senses Lipid Packing Defects and Induces Lateral Expansion of Lipids Leading to Membrane Remodeling, J. Biol. Chem., 288 (2013) 20883-20895. [30] T.L. Williams, L.C. Serpell, Membrane and surface interactions of Alzheimer’s Aβ peptide – insights into the mechanism of cytotoxicity, FEBS J., 278 (2011) 3905-3917. [31] C.M. Yip, A.A. Darabie, J. McLaurin, Aβ42-Peptide Assembly on Lipid Bilayers, J. Mol. Biol., 318 (2002) 97-107. [32] P.M. Pifer, E.A. Yates, J. Legleiter, Point mutations in Abeta result in the formation of distinct polymorphic aggregates in the presence of lipid bilayers, PLoS One, 6 (2011) e16248. [33] E.A. Yates, E.M. Cucco, J. Legleiter, Point Mutations in A beta Induce Polymorphic Aggregates at Liquid/Solid Interfaces, ACS Chem. Neurosci., 2 (2011) 294-307. [34] R. Williamson, C. Sutherland, Neuronal Membranes are Key to the Pathogenesis of Alzheimers Disease: the Role of Both Raft and Non-Raft Membrane Domains, Curr. Alzheimer Res., 8 (2011) 213-221. [35] J.D. Harper, S.S. Wong, C.M. Lieber, P.T. Lansbury, Assembly of A beta amyloid protofibrils: An in vitro model for a possible early event in Alzheimer′s disease, Biochemistry, 38 (1999) 8972-8980. [36] H.A. Lashuel, D. Hartley, B.M. Petre, T. Walz, P.T. Lansbury, Neurodegenerative disease - Amyloid pores from pathogenic mutations, NATURE, 418 (2002) 291-291. [37] L. Hendriks, C.M. van Duijn, P. Cras, M. Cruts, W. Van Hul, F. van Harskamp, A. Warren, M.G. McInnis, S.E. Antonarakis, J.-J. Martin, A. Hofman, C. Van Broeckhoven, Presenile dementia and cerebral haemorrhage linked to a mutation at codon 692 of the [beta]-amyloid precursor protein gene, Nat. Genet., 1 (1992) 218-221. [38] C. Nilsberth, A. Westlind-Danielsson, C.B. Eckman, M.M. Condron, K. Axelman, C. Forsell, C. Stenh, J. Luthman, D.B. Teplow, S.G. Younkin, J. Naslund, L. Lannfelt, The ′Arctic′ APP mutation (E693G) causes Alzheimer′s disease by enhanced A[beta] protofibril formation, Nat. Neurosci., 4 (2001) 887-893. [39] E. Levy, M. Carman, I. Fernandez-Madrid, M. Power, I. Lieberburg, S. van Duinen, G. Bots, W. Luyendijk, B. Frangione, Mutation of the Alzheimer′s disease amyloid gene in hereditary cerebral hemorrhage, Dutch type, Science, 248 (1990) 1124-1126. [40] L. Miravalle, T. Tokuda, R. Chiarle, G. Giaccone, O. Bugiani, F. Tagliavini, B. Frangione, J. Ghiso, Substitutions at Codon 22 of Alzheimer′s Aβ Peptide Induce Diverse Conformational Changes and Apoptotic Effects in Human Cerebral Endothelial Cells, J. Biol. Chem., 275 (2000) 27110-27116. [41] T.J. Grabowski, H.S. Cho, J.P.G. Vonsattel, G.W. Rebeck, S.M. Greenberg, Novel amyloid precursor protein mutation in an Iowa family with dementia and severe cerebral amyloid angiopathy, Annals of Neurology, 49 (2001) 697-705. [42] W.E. Van Nostrand, J.P. Melchor, H.S. Cho, S.M. Greenberg, G.W. Rebeck, Pathogenic effects of D23N Iowa mutant amyloid b-protein, J. Biol. Chem., 276 (2001) 32860-32866. [43] G. Bitan, S.S. Vollers, D.B. Teplow, Elucidation of Primary Structure Elements Controlling Early Amyloid β-Protein Oligomerization, J. Biol. Chem., 278 (2003) 34882-34889. [44] W. Han, Y.-D. Wu, A Strand-Loop-Strand Structure Is a Possible Intermediate in Fibril Elongation:  Long Time Simulations of Amyloid-β Peptide (10−35), J. Am. Chem. Soc., 127 (2005) 15408-15416. [45] A.T. Petkova, Y. Ishii, J.J. Balbach, O.N. Antzutkin, R.D. Leapman, F. Delaglio, R. Tycko, A structural model for Alzheimer′s β-amyloid fibrils based on experimental constraints from solid state NMR, Proc. Natl. Acad. Sci. U S A, 99 (2002) 16742-16747. [46] T. Luhrs, C. Ritter, M. Adrian, D. Riek-Loher, B. Bohrmann, H. Dobeli, D. Schubert, R. Riek, 3D structure of Alzheimer′s amyloid-beta(1-42) fibrils, Proc. Natl. Acad. Sci. U S A, 102 (2005) 17342-17347. [47] S. Shivaprasad, R. Wetzel, An Intersheet Packing Interaction in Aβ Fibrils Mapped by Disulfide Cross-Linking†, Biochemistry, 43 (2004) 15310-15317. [48] W.P. Esler, E.R. Stimson, J.R. Ghilardi, Y.-A. Lu, A.M. Felix, H.V. Vinters, P.W. Mantyh, J.P. Lee, J.E. Maggio, Point Substitution in the Central Hydrophobic Cluster of a Human β-Amyloid Congener Disrupts Peptide Folding and Abolishes Plaque Competence†, Biochemistry, 35 (1996) 13914-13921. [49] L.M. Luheshi, G.G. Tartaglia, A.-C. Brorsson, A.P. Pawar, I.E. Watson, F. Chiti, M. Vendruscolo, D.A. Lomas, C.M. Dobson, D.C. Crowther, Systematic In Vivo Analysis of the Intrinsic Determinants of Amyloid β Pathogenicity, PLoS Biol, 5 (2007) e290. [50] A.D. Williams, E. Portelius, I. Kheterpal, J.-t. Guo, K.D. Cook, Y. Xu, R. Wetzel, Mapping Aβ Amyloid Fibril Secondary Structure Using Scanning Proline Mutagenesis, J. Mol. Biol., 335 (2004) 833-842. [51] L.O. Tjernberg, J. Näslund, F. Lindqvist, J. Johansson, A.R. Karlström, J. Thyberg, L. Terenius, C. Nordstedt, Arrest of -Amyloid Fibril Formation by a Pentapeptide Ligand, J. Biol. Chem., 271 (1996) 8545-8548. [52] J.M. Borreguero, B. Urbanc, N.D. Lazo, S.V. Buldyrev, D.B. Teplow, H.E. Stanley, Folding events in the 21-30 region of amyloid-beta-protein (A beta) studied in silico, Proc. Natl. Acad. Sci. U. S. A., 102 (2005) 6015-6020. [53] H.D. Nguyen, C.K. Hall, Molecular dynamics simulations of spontaneous fibril formation by random-coil peptides, Proc. Natl. Acad. Sci. U. S. A., 101 (2004) 16180-16185. [54] B. Urbanc, L. Cruz, S. Yun, S.V. Buldyrev, G. Bitan, D.B. Teplow, H.E. Stanley, In silico study of amyloid {beta}-protein folding and oligomerization, Proc. Natl. Acad. Sci. U. S. A., 101 (2004) 17345-17350. [55] B. Urbanc, M. Betnel, L. Cruz, H. Li, E.A. Fradinger, B.H. Monien, G. Bitan, Structural Basis for Aβ1–42 Toxicity Inhibition by Aβ C-Terminal Fragments: Discrete Molecular Dynamics Study, J. Mol. Biol., 410 (2011) 316-328. [56] J. Gsponer, U. Haberthur, A. Caflisch, The role of side-chain interactions in the early steps of aggregation: Molecular dynamics simulations of an amyloid- forming peptide from the yeast prion Sup35, Proc. Natl. Acad. Sci. U. S. A., 100 (2003) 5154-5159. [57] W. Hwang, S. Zhang, R.D. Kamm, M. Karplus, Kinetic control of dimer structure formation in amyloid fibrillogenesis, Proc. Natl. Acad. Sci. U. S. A., 101 (2004) 12916-12921. [58] M.M. Dedmon, K. Lindorff-Larsen, J. Christodoulou, M. Vendruscolo, C.M. Dobson, Mapping Long-Range Interactions in a-Synuclein using Spin-Label NMR and Ensemble Molecular Dynamics Simulations, J. Am. Chem. Soc., 127 (2005) 476-477. [59] D.W. Li, L. Han, S.H. Huo, Structural and pathway complexity of beta-strand reorganization within aggregates of human transthyretin(105-115) peptide, J. Phys. Chem. B, 111 (2007) 5425-5433. [60] D.L. Mobley, D.L. Cox, R.R.P. Singh, M.W. Maddox, M.L. Longo, Modeling amyloid beta-peptide insertion into lipid bilayers, Biophys. J., 86 (2004) 3585-3597. [61] S. Jang, S. Shin, Computational study on the structural diversity of amyloid beta peptide (A beta(10-35)) oligomers, J. Phys. Chem. B, 112 (2008) 3479-3484. [62] A. Suenaga, Replica-exchange molecular dynamics simulations for a small-sized protein folding with implicit solvent, Comp. Theor. Chem., 634 (2003) 235-241. [63] A. Barducci, R. Chelli, P. Procacci, V. Schettino, F.L. Gervasio, M. Parrinello, Metadynamics Simulation of Prion Protein: Beta-Structure Stability and the Early Stages of Misfolding, J. Am. Chem. Soc., 128 (2006) 2705-2710. [64] Y.-S. Lin, Gregory R. Bowman, Kyle A. Beauchamp, Vijay S. Pande, Investigating How Peptide Length and a Pathogenic Mutation Modify the Structural Ensemble of Amyloid Beta Monomer, Biophys. J., 102 (2012) 315-324. [65] Y.S. Lin, V.S. Pande, Effects of Familial Mutations on the Monomer Structure of A beta(42), Biophys. J., 103 (2012) L47-L49. [66] J.A. Lemkul, D.R. Bevan, A comparative molecular dynamics analysis of the amyloid β-peptide in a lipid bilayer, Arch. Biochem. Biophys., 470 (2008) 54-63. [67] Y. Xu, J. Shen, X. Luo, W. Zhu, K. Chen, J. Ma, H. Jiang, Conformational transition of amyloid β-peptide, Proc. Natl. Acad. Sci. U S A, 102 (2005) 5403-5407. [68] H.-H. Tsai, M. Reches, C.-J. Tsai, K. Gunasekaran, E. Gazit, R. Nussinov, Energy landscape of amyloidogenic peptide oligomerization by parallel-tempering molecular dynamics simulation: Significant role of Asn ladder, Proc. Natl. Acad. Sci. U S A, 102 (2005) 8174-8179. [69] S. Gnanakaran, R. Nussinov, A.E. Garcia, Atomic-level description of amyloid beta-dimer formation, J. Am. Chem. Soc., 128 (2006) 2158-2159. [70] N.G. Sgourakis, Y.L. Yan, S.A. McCallum, C.Y. Wang, A.E. Garcia, The Alzheimer′s peptides A beta 40 and 42 adopt distinct conformations in water: A combined MD/NMR study, J. Mol. Biol., 368 (2007) 1448-1457. [71] G. Bellesia, J.E. Shea, What Determines the Structure and Stability of KFFE Monomers, Dimers, and Protofibrils?, Biophys. J., 96 (2009) 875-886. [72] A.S. Reddy, A. Izmitli, J.J. de Pablo, Effect of trehalose on amyloid beta (29-40)-membrane interaction, J. Chem. Phys., 131 (2009) 085101-085108. [73] J.A. Lemkul, D.R. Bevan, Perturbation of membranes by the amyloid beta-peptide - a molecular dynamics study, FEBS J., 276 (2009) 3060-3075. [74] R. Friedman, R. Pellarin, A. Caflisch, Amyloid Aggregation on Lipid Bilayers and Its Impact on Membrane Permeability, J. Mol. Biol., 387 (2009) 407-415. [75] L. Qiu, C. Buie, A. Reay, M.W. Vaughn, K.H. Cheng, Molecular Dynamics Simulations Reveal the Protective Role of Cholesterol in β-Amyloid Protein-Induced Membrane Disruptions in Neuronal Membrane Mimics, J. Phys. Chem. B, 115 (2011) 9795-9812. [76] S. Dante, T. Hau, A. Brandt, N.A. Dencher, Membrane Fusogenic Activity of the Alzheimer′s Peptide A[beta](1-42) Demonstrated by Small-Angle Neutron Scattering, J. Mol. Biol., 376 (2008) 393-404. [77] S.b. Côté, P. Derreumaux, N. Mousseau, Distinct Morphologies for Amyloid Beta Protein Monomer: Aβ1–40, Aβ1–42, and Aβ1–40(D23N), J. Chem. Theory Comput., 7 (2011) 2584-2592. [78] L. Xu, S.S. Shan, X.C. Wang, Single Point Mutation Alters the Microstate Dynamics of Amyloid beta-Protein A beta 42 as Revealed by Dihedral Dynamics Analyses, J. Phys. Chem. B, 117 (2013) 6206-6216. [79] N. Miyashita, J.E. Straub, D. Thirumalai, Structures of β-Amyloid Peptide 1−40, 1−42, and 1−55—the 672−726 Fragment of APP—in a Membrane Environment with Implications for Interactions with γ-Secretase, J. Am. Chem. Soc., 131 (2009) 17843-17852. [80] S. Côté, R. Laghaei, P. Derreumaux, N. Mousseau, Distinct Dimerization for Various Alloforms of the Amyloid-Beta Protein: Aβ1–40, Aβ1–42, and Aβ1–40(D23N), J. Phys. Chem. B, 116 (2012) 4043-4055. [81] S.H. Chong, J. Yim, S. Ham, Structural heterogeneity in familial Alzheimer′s disease mutants of amyloid-beta peptides, Mol. Biosyst., 9 (2013) 997-1003. [82] C. Velez-Vega, F.A. Escobedo, Characterizing the Structural Behavior of Selected Aβ-42 Monomers with Different Solubilities, J. Phys. Chem. B, 115 (2011) 4900-4910. [83] W. Im, M. Feig, C.L. Brooks, An implicit membrane generalized born theory for the study of structure, stability, and interactions of membrane proteins, Biophys. J., 85 (2003) 2900-2918. [84] F. Misiti, B. Sampaolese, M. Pezzotti, S. Marini, M. Coletta, L. Ceccarelli, B. Giardina, M.E. Clementi, Aβ(31–35) peptide induce apoptosis in PC 12 cells: Contrast with Aβ(25–35) peptide and examination of underlying mechanisms, Neurochem. Int., 46 (2005) 575-583. [85] M.E. Clementi, S. Marini, M. Coletta, F. Orsini, B. Giardina, F. Misiti, Aβ(31–35) and Aβ(25–35) fragments of amyloid beta-protein induce cellular death through apoptotic signals: Role of the redox state of methionine-35, FEBS Lett., 579 (2005) 2913-2918. [86] M.-C. Lin, T. Mirzabekov, B.L. Kagan, Channel Formation by a Neurotoxic Prion Protein Fragment, J. Biol. Chem., 272 (1997) 44-47. [87] B.L. Kagan, Y. Hirakura, R. Azimov, R. Azimova, M.-C. Lin, The channel hypothesis of Alzheimer’s disease: current status, Peptides, 23 (2002) 1311-1315. [88] M.-c.A. Lin, B.L. Kagan, Electrophysiologic properties of channels induced by Aβ25–35 in planar lipid bilayers, Peptides, 23 (2002) 1215-1228. [89] K. Sato, A. Wakamiya, T. Maeda, K. Noguchi, A. Takashima, K. Imahori, Correlation among Secondary Structure, Amyloid Precursor Protein Accumulation, and Neurotoxicity of Amyloid β(25–35) Peptide as Analyzed by Single Alanine Substitution, J. Biochem., 118 (1995) 1108-1111. [90] H.-H.G. Tsai, J.-B. Lee, S.-S. Tseng, X.-A. Pan, Y.-C. Shih, Folding and membrane insertion of amyloid-beta (25–35) peptide and its mutants: Implications for aggregation and neurotoxicity, Protein Struct. Funct. Bioinfo., 78 (2010) 1909-1925. [91] H.-H.G. Tsai, J.-B. Lee, Y.-C. Shih, L. Wan, F.-K. Shieh, C.-Y. Chen, Location and Conformation of Amyloid β(25–35) Peptide and its Sequence-Shuffled Peptides within Membranes: Implications for Aggregation and Toxicity in PC12 Cells, ChemMedChem, 9 (2014) 1002-1011. [92] W.P. Im, M.S. Lee, C.L. Brooks, Generalized born model with a simple smoothing function, J. Comput. Chem., 24 (2003) 1691-1702. [93] W. Im, C.L. Brooks, Interfacial folding and membrane insertion of designed peptides studied by molecular dynamics simulations, Proceedings of the National Academy of Sciences of the United States of America, 102 (2005) 6771-6776. [94] T. Lazaridis, M. Karplus, Effective energy function for proteins in solution, Proteins-Structure Function and Genetics, 35 (1999) 133-152. [95] A. Kent, A.K. Jha, J.E. Fitzgerald, K.F. Freed, Benchmarking implicit solvent folding simulations of the amyloid beta(10-35) fragment, J. Phys. Chem. B, 112 (2008) 6175-6186. [96] W.C. Still, A. Tempczyk, R.C. Hawley, T. Hendrickson, Semianalytical treatment of solvation for molecular mechanics and dynamics, J. Am. Chem. Soc., 112 (1990) 6127-6129. [97] A.D. MacKerell, D. Bashford, M. Bellott, R.L. Dunbrack, J.D. Evanseck, M.J. Field, S. Fischer, J. Gao, H. Guo, S. Ha, D. Joseph-McCarthy, L. Kuchnir, K. Kuczera, F.T.K. Lau, C. Mattos, S. Michnick, T. Ngo, D.T. Nguyen, B. Prodhom, W.E. Reiher, B. Roux, M. Schlenkrich, J.C. Smith, R. Stote, J. Straub, M. Watanabe, J. Wiorkiewicz-Kuczera, D. Yin, M. Karplus, All-atom empirical potential for molecular modeling and dynamics studies of proteins, J. Phys. Chem. B, 102 (1998) 3586-3616. [98] A.D. MacKerell, M. Feig, C.L. Brooks, Improved treatment of the protein backbone in empirical force fields, J. Am. Chem. Soc., 126 (2004) 698-699. [99] S.F. Mark, C. Qiang, The use of a generalized born model for the analysis of protein conformational transitions: A comparative study with explicit solvent simulations for chemotaxis Y protein (CheY), J. Comput. Chem., 27 (2006) 1923-1943. [100] J.-P. Ryckaert, G. Ciccotti, H.J.C. Berendsen, Numerical integration of the cartesian equations of motion of a system with constraints: Molecular dynamics of n-alkanes, J. Comp. Phys., 23 (1977) 327-341. [101] Y. Sugita, Y. Okamoto, Replica-exchange multicanonical algorithm and multicanonical replica-exchange method for simulating systems with rough energy landscape, Chem. Phys. Lett., 329 (2000) 261-270. [102] Y. Sugita, Y. Okamoto, Replica-exchange molecular dynamics method for protein folding, Chem. Phys. Lett., 314 (1999) 141-151. [103] F. Rao, A. Caflisch, Replica exchange molecular dynamics simulations of reversible folding, J. Chem. Phys., 119 (2003) 4035-4042. [104] A.E. Garcia, J.N. Onuchic, Folding a protein in a computer: An atomic description of the folding/unfolding of protein A, Proc. Natl. Acad. Sci. USA, 100 (2003) 13898-13903. [105] R.H. Zhou, Trp-cage: Folding free energy landscape in explicit water, Proc. Natl. Acad. Sci. USA, 100 (2003) 13280-13285. [106] J.W. Pitera, W. Swope, Understanding folding and design: Replica-exchange simulations of ”Trp-cage” fly miniproteins, Proc. Natl. Acad. Sci. USA, 100 (2003) 7587-7592. [107] A.K. Felts, Y. Harano, E. Gallicchio, R.M. Levy, Free energy surfaces of beta-hairpin and alpha-helical peptides generated by replica exchange molecular dynamics with the AGBNP implicit solvent model, Proteins, 56 (2004) 310-321. [108] M. Feig, J. Karanicolas, I.C.L. Brooks, MMTSB Tool Set: enhanced sampling and multiscale modeling methods for applications in structural biology, J. Mol. Graphics Model., 22 (2004) 377-395. [109] S. Kumar, J.M. Rosenberg, D. Bouzida, R.H. Swendsen, P.A. Kollman, Multidimensional Free-Energy Calculations Using the Weighted Histogram Analysis Method, J. Comput. Chem., 16 (1995) 1339-1350. [110] J.D. Chodera, W.C. Swope, J.W. Pitera, C. Seok, K.A. Dill, Use of the weighted histogram analysis method for the analysis of simulated and parallel tempering simulations, Journal of Chemical Theory and Computation, 3 (2007) 26-41. [111] W. Kabsch, C. Sander, Dictionary of protein secondary structure: pattern recognition of hydrogen-bonded and geometrical features, Biopolymers, 22 (1983) 2577-2637. [112] S.J. Hubbard, J.M. Thornton, ′NACCESS′, computer program, (1993). [113] R.L. Frozza, A.P. Horn, J.B. Hoppe, F. Simão, D. Gerhardt, R.A. Comiran, C.G. Salbego, A Comparative Study of β-Amyloid Peptides Aβ1-42 and Aβ25-35 Toxicity in Organotypic Hippocampal Slice Cultures, Neurochem. Res., 34 (2008) 295-303. [114] C.D. Anfuso, G. Assero, G. Lupo, A. Nicotra, G. Cannavo, R.P. Strosznajder, P. Rapisarda, R. Pluta, M. Alberghina, Amyloid beta(1-42) and its beta(25-35) fragment induce activation and membrane translocation of cytosolic phospholipase A2 in bovine retina capillary pericytes, Biochim. Biophys. Acta, Protein Struct. Mol. Enzymol., 1686 (2004) 125-138. [115] C.J. Pike, J.W.-W. Andrea, K. Joseph, H.C. David, G.G. Charles, W.C. Carl, Structure-Activity Analyses of b-Amyloid Peptides: Contributions of the b25-35 Region to Aggregation and Neurotoxicity, J. Neurochem., 64 (1995) 253-265. [116] R. Buchet, E. Tavitian, D. Ristig, R. Swoboda, U. Stauss, H.U. Gremlich, L. de La Fourniere, M. Staufenbiel, P. Frey, D.A. Lowe, Conformations of synthetic beta peptides in solid state and in aqueous solution: relation to toxicity in PC12 cells, Biochimica et biophysica acta. Molecular basis of disease, 1315 (1996) 40-46. [117] T. Kubo, S. Nishimura, Y. Kumagae, I. Kaneko, In vivo conversion of racemized beta-amyloid ([D-Ser(26)]A beta 1-40) to truncated and toxic fragments ([D-Ser(26)]A beta 25-35/40) and fragment presence in the brains of Alzheimer′s patients, J. Neurosci. Res., 70 (2002) 474-483. [118] L. Millucci, L. Ghezzi, G. Bernardini, A. Santucci, Conformations and Biological Activities of Amyloid Beta Peptide 25-35, Curr. Protein Pept. Sci., 11 (2010) 54-67. [119] C.-W. Tsai, N.-Y. Hsu, C.-H. Wang, C.-Y. Lu, Y. Chang, H.-H.G. Tsai, R.-C. Ruaan, Coupling Molecular Dynamics Simulations with Experiments for the Rational Design of Indolicidin-Analogous Antimicrobial Peptides, J. Mol. Biol., 392 (2009) 837-854. [120] T. Takeda, D.K. Klimov, Computational Backbone Mutagenesis of Aβ Peptides: Probing the Role of Backbone Hydrogen Bonds in Aggregation, J. Phys. Chem. B, 114 (2010) 4755-4762. [121] B.P. Orner, L. Liu, R.M. Murphy, L.L. Kiessling, Phage Display Affords Peptides that Modulate β-Amyloid Aggregation, J. Am. Chem. Soc., 128 (2006) 11882-11889. [122] M. Lee, F. Bard, K. Johnson-Wood, C. Lee, K. Hu, S.G. Griffith, R.S. Black, D. Schenk, P. Seubert, Aβ42 immunization in Alzheimer′s disease generates Aβ N-terminal antibodies, Annals of Neurology, 58 (2005) 430-435. [123] A. Maiorana, T. Marino, V. Minicozzi, S. Morante, N. Russo, A micro-environmental study of the Zn+2-A beta(1-16) structural properties, Biolphys. Chem., 182 (2013) 86-93. [124] K.A. Ball, A.H. Phillips, P.S. Nerenberg, N.L. Fawzi, D.E. Wemmer, T. Head-Gordon, Homogeneous and Heterogeneous Tertiary Structure Ensembles of Amyloid-β Peptides, Biochemistry, 50 (2011) 7612-7628. [125] F. Chiti, M. Calamai, N. Taddei, M. Stefani, G. Ramponi, C.M. Dobson, Studies of the aggregation of mutant proteins in vitro provide insights into the genetics of amyloid diseases, Proc. Natl. Acad. Sci. U S A, 99 (2002) 16419-16426. [126] M. López de la Paz, K. Goldie, J. Zurdo, E. Lacroix, C.M. Dobson, A. Hoenger, L. Serrano, De novo designed peptide-based amyloid fibrils, Proc. Natl. Acad. Sci. U S A, 99 (2002) 16052-16057. [127] M.B. Ulmschneider, M.S.P. Sansom, A. Di Nola, Properties of integral membrane protein structures: Derivation of an implicit membrane potential, Protein Struct. Funct. Bioinfo., 59 (2005) 252-265. [128] R. Liu, C. McAllister, Y. Lyubchenko, M.R. Sierks, Residues 17–20 and 30–35 of beta-amyloid play critical roles in aggregation, Journal of Neuroscience Research, 75 (2004) 162-171. [129] S.L. Bernstein, T. Wyttenbach, A. Baumketner, J.-E. Shea, G. Bitan, D.B. Teplow, M.T. Bowers, Amyloid β-Protein:  Monomer Structure and Early Aggregation States of Aβ42 and Its Pro19 Alloform, J. Am. Chem. Soc., 127 (2005) 2075-2084. [130] T. Kohno, K. Kobayashi, T. Maeda, K. Sato, A. Takashima, Three-Dimensional Structures of the Amyloid β Peptide (25−35) in Membrane-Mimicking Environment‡, Biochemistry, 35 (1996) 16094-16104. [131] A.M. D′Ursi, M.R. Armenante, R. Guerrini, S. Salvadori, G. Sorrentino, D. Picone, Solution Structure of Amyloid β-Peptide (25−35) in Different Media, J. Med. Chem., 47 (2004) 4231-4238. [132] G.H. Wei, J.E. Shea, Effects of solvent on the structure of the Alzheimer amyloid-beta(25-35) peptide, Biophys. J., 91 (2006) 1638-1647. [133] S. Dante, T. Hauss, N.A. Dencher, Insertion of Externally Administered Amyloid β Peptide 25−35 and Perturbation of Lipid Bilayers†, Biochemistry, 42 (2003) 13667-13672. [134] E.G. Hutchinson, J.M. Thornton, A revised set of potentials for β-turn formation in proteins, Protein Science, 3 (1994) 2207-2216. [135] S. Hashioka, A. Monji, T. Ueda, S. Kanba, H. Nakanishi, Amyloid-[beta] fibril formation is not necessarily required for microglial activation by the peptides, Neurochem. Int., 47 (2005) 369-376. [136] E. Terzi, G. Holzemann, J. Seelig, Reversible Random Coil Beta-Sheet Transition of the Alzheimer Beta-Amyloid Fragment (25-35), Biochemistry, 33 (1994) 1345-1350. [137] We generally suspend the cell in culture media and then plating the cell into the wells. PC-12 is an attached cell line and we need to perform trypsinization to detach the cell from the cell culture plate. In this step, we generally try our best to prepare single cell suspension; however, there are always cells cluster together. When plating the cells, this will cause increase cell number and cause a cell survival greater than 100%. Of course, it is very possible that some wells have fewer cell numbers. To minimize this effect, we generally perform 8 different repeats to normalize the data. And the results showed here is the average of the three different experiments performed. All three different experiments showed the same trend of cytotoxicity of Aβ peptides. [138] W.C. Wimley, S.H. White, Experimentally Determined Hydrophobicity Scale for Proteins at Membrane Interfaces, Nat. Struct. Biol., 3 (1996) 842-848. [139] M. Fernández-Vidal, S. Jayasinghe, A.S. Ladokhin, S.H. White, Folding Amphipathic Helices Into Membranes: Amphiphilicity Trumps Hydrophobicity, J. Mol. Biol., 370 (2007) 459-470. [140] Abeta(25-35) and Abeta(35-25) peptides are simulated in an explicit water-membrane environment. One system consists of one peptide, one zwitterionic POPC lipid bilayers composed of 96 lipids and water molecules. The initial configurations of peptides are adopted from the more populated structures of our GBSW/REMD simulations. To obtain better statistics, two most populated configurations were simulated. One has the peptide’s helix orientation parallel to membrane surface and the peptide located within the interface. The other one has peptide’s helix orientation nearly parallel to membrane normal and its helical C-terminal inserted within membrane. The potential functions of peptides, lipids as well as ions were modeled by CHARMM36 all atom force field. A MD simulation time of 50 ns was performed for each system and the last 30 ns trajectory is used for the statistical analysis. The details will be published elsewhere. [141] S. Jaud, M. Fernandez-Vidal, I. Nilsson, N.M. Meindl-Beinker, N.C. Hubner, D.J. Tobias, G. von Heijne, S.H. White, Insertion of short transmembrane helices by the Sec61 translocon, Proc. Natl. Acad. Sci. U. S. A., 106 (2009) 11588-11593. [142] M.B. Ulmschneider, J.C. Smith, J.P. Ulmschneider, Peptide Partitioning Properties from Direct Insertion Studies, Biophys. J., 98 (2010) L60-L62.
指導教授	蔡惠旭(Hui-Hsu Gavin Tsai)	審核日期	2015-1-28
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