臺灣博碩士論文加值系統

老年斑塊和纖維沉澱是阿茲海默症特徵而且它們被認為和阿茲海默症的神經毒性有關聯。貝他類澱粉胜肽則是老年斑塊和纖維沉澱的主要成分。銅離子和貝他類澱粉胜肽鍵結被認為是產生神經毒性的貝他類澱粉胜肽的重要角色。但是許多銅離子和貝他類澱粉胜肽鍵結的特性和位置都還沒有明確的答案且具有一些爭議。在我們的研究中，提供了一些銅離子和貝他類澱粉胜肽上的組氨酸(His)的配位結構,而這些結構有可能造成纖維沉澱。

Amyloid-β peptide (Aβ) is the principal constituent of plaques and fibrils associated with Alzheimer’s disease (AD) and is thought to be responsible for the neurotoxicity associated with the disease. Copper binding to Aβ has been hypothesized to play an important role in the neruotoxicity of Aβ. However, many properties of copper binding to Aβ have not been elucidated clearly, and the location of copper binding sites on Aβ is also in controversy. In this work, several possible models containing copper(II) coordinating with His residues of Aβ related to fibril formation were proposed, and the results provided a viewpoint to discuss formation of the fibril.

Acknowledgement--------------------------------------------------------------------------i
Abstract------------------------------------------------------------------------------------------iii
Contents----------------------------------------------------------------------------------------v
Tables--------------------------------------------------------------------------------------------vii
Figures-----------------------------------------------------------------------------------------viii
Chapter 1 Introduction------------------------------------------------------------------01
Chapter 2 Theoretical Background-------------------------------------------------07
2.1 The Born-Oppenheimer approximation--------------------------------------------07
2.2 Density-Functional Theory----------------------------------------------------------08
2.2.1 The Hohenberg-Kohn Theory---------------------------------------------08
2.2.2 Local density approximation (LDA) ----------------------------------------09
2.2.3 Hybrid functionals ----------------------------------------------------------09
2.3 Basis sets----------------------------------------------------------------------------09
2.3.1 Slater-type orbital (STO) ----------------------------------------------------10
2.3.2 Gaussian Type Orbital (GTO) -----------------------------------------------10
2.3.3 Double-ξ, Triple-ξ, Quadruple-ξ---------------------------------------------11
2.3.4 Split Valence Basis Set ---------------------------------------------------------11
2.3.5 Polarized basis Set -------------------------------------------------------11
2.3.6 Diffuse Sets --------------------------------------------------------12
2.4 Semiempirical Method--------------------------------------------------------12
2.4.1 Parameterized Method 3 (PM3) ----------------------------------13
Chapter 3 Model and Calculational Method ------------------------------14
3.1 Models---------------------------------------------------------------------------------14
3.2 Analysis method - Ramachandran plot ---------------------------------------------17
Chapter 4 Results and Discussion-------------------------------------------------19
4.1 Coordination mode of Cu2+-Aβ complex ------------------------------------------20
4.2 Intermolecular backbone hydrogen bonds ------------------------------------27
4.3 Permutation combination and Ramachandran plot----------------------------32
4.4 The conformation change of Aβ42 when coordinated to copper(II) -------------52 Chapter 5 Conclusions -----------------------------------------------------------------56
References------------------------------------------------------------------------------------57
Tables
Table 1. The comparison among the nine optimized structures including the energies, binding atoms and the dihedral angles of the distorted square planar.
--------------------------------------------------------------------------------------------25
Table 2. The location of the backbone H-bonds in the four extra Gly residues and the types of the coordinated nitrogen atoms and energies of three structures. ---------------------------------------------------------------------------------------------31
Figures
Figure 1 The microscope of AD patients’ brain slice taken from Reference1. --------04
Figure 2 The amino acid sequence of Aβ(1-42) with His6, 13 and 14 labeled as the metal binding sites.-------------------------------------------------------------------05
Figure 3 The molecular structure of Histidine with Nπ and Nτ of Histidine imidazole ring labeled as candidates for metal binding ligands. --------------------------06
Figure 4 The scheme to generate the models of Aβ42 aggregates with copper-bonding motifs used in this study based on three structures of copper coordinating with a His-His dipeptide suggested in Reference 22 and 23 as labeled as “a”, “b”and “c”. ------------------------------------------------------------------------16
Figure 5 The schematic plot for the definition of Φ and Ψ angles in Ramachandran plot, which is the dihedral angles of C-N-αC-C and N-αC-C-N, respectively.-------------------------------------------------------------------------------------------18
Figure 6 “a - Nπ” with 4N coordination (4Nπ).--------------------------------------------22
Figure7 “a – NτNπ” with 3N1O coordination (2Nπ,Nτ, OB)-------------------------22
Figure 8 “a – Nτ” with 3N1O coordination (Nπ, 2Nτ,OB).-----------------------------22
Figure 9 “b - Nπ” with 3N1O coordination (Nπ, 2Nτ,OB).-----------------------------23
Figure 10 “b - NτNπ” with 4N coordination (Nπ,3Nτ).-------------------------------23
Figure 11 “b - Nτ” with 4N coordination (4Nτ).------------------------------------------23
Figure 12 “c - Nπ” with 4N coordination (2Nπ,Nτ,NB-).-------------------------------24
Figure 13 “c - NτNπ” with 4N coordination (2Nπ,Nτ,NB-).--------------------------24
Figure 14 “c - Nτ” with 4N coordination (2Nπ,Nτ,NB-).-------------------------------24
Figure 15 The definition of dihedral angle. ---------------------------------------------------26
Figure 16 The structure of “a- NτNπ” attaching four Gly residues to the C-terminal of the two His13-His14 strands. ------------------------------------------------------28
Figure 17 The structure of “b- NτNπ” attaching four Gly residues to the C-terminal of the two His13-His14 strands. ------------------------------------------------------29
Figure 18 The structure of “c- Nτ” attaching four Gly residues to the C-terminal of the two His13-His14 strands.-----------------------------------------------------------30
Figure 19 The aggregation motif used in the current study, representing two His13-His14 strands coordinated with copper (II), referred as “4N” model. -----------------34
Figure 20 The permutation combination of “1-series” using His13 as bridge.------------------------------------------------------------------------------------------35
Figure 21 The scheme for the formation of “b-NτNπ-1-b-Nτ” and “b-NτNπ-1''-b-Nτ”.------------------------------------------------------------------------------------------36
Figure 22 The example of “b-NτNπ-1-b-Nτ” formation. -----------------------------------37
Figure 23 The example of “b-NτNπ-1''-b-Nτ” formation. ----------------------------------37
Figure 24 The permutation combination of “2-series” using His13’ as bridge.------------------------------------------------------------------------------------------38
Figure 25 The scheme for the formation of “b-NτNπ-2-b-Nτ” ------------------------------------------------------------------------------------------39
Figure 26 The example of “b-NτNπ-2-b-Nτ” formation. ----------------------------------40
Figure 27 The example of “b-NτNπ-2''-b-Nτ” formation. -------------------------------- 40 Figure 28 The permutation combination of “3-series” using His14 as bridge. ----------41
Figure 29 The scheme for the formation of “b-NτNπ-3-b-Nτ” and “b-NτNπ-3''-b-Nτ”.------------------------------------------------------------------------------------------42
Figure 30 The example of “b-NτNπ-3-b-Nτ” formation. -----------------------------------43
Figure 31 The example of “b-NτNπ-3''-b-Nτ” formation. ----------------------------------43
Figure 32 The permutation combination of “4-series” using His14’ as bridge. ----------44
Figure 33 The scheme for the formation of “b-NτNπ-4-b-Nτ” and b-NτNπ-4''-b-Nτ”.------------------------------------------------------------------------------------------45
Figure 34 The example of “b-NτNπ-4-b-Nτ” formation. ----------------------------------46
Figure 35 The example of “b-NτNπ-4''-b-Nτ” formation. ---------------------------------46 Figure 36 The Ramachandran plot of the five structures chose from the permutation combination of the 1-series. --------------------------------------------------------48
Figure 37 The Ramachandran plot of the two structures chose from the permutation combination of the 1’-series. -------------------------------------------------------48
Figure 38 The Ramachandran plot of the four structures chose from the permutation combination of the 2-series. --------------------------------------------------------49
Figure 39 The Ramachandran plot of the two structures chose from the permutation combination of the 2’-series. -------------------------------------------------------49
Figure 40 The Ramachandran plot of the ten structures chose from the permutation combination of the 3-series. --------------------------------------------------------50
Figure 41 The Ramachandran plot of the four structures chose from the permutation combination of the 3’-series. -------------------------------------------------------50
Figure 42 The Ramachandran plot of the six structures chose from the permutation combination of the 4-series. --------------------------------------------------------51
Figure 43 The side view of “c-Nτ-3-c-NτNπ” with the intermolecular hydrogen bonds shown in green dashed lines. -------------------------------------------------------54
Figure 44 The front view of “c-Nτ-3-c-NτNπ”. There are two distorted square planes with metal-binding atoms as “2Nπ, Nτ, NB- ”.------------------------------------55

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