| Along with the rapid growth of the oldest age groups of the population, AD has become the leading neurodegenerative disorder which seriously threatens the health of the aged worldwide. The epidemiologic data indicate that AD is the neurodegenerative disease with the highest rate of incidence; and according to a conservative estimate, just in 2006, AD affected about 4.6 million new patients worldwide. Facing up to the dramatic rise in life expectancy and the devastation to human health, high treatment cost and potential prevalence of AD, many countries, especially the developed countries, have treated AD as a gravely strategic problem which menaces the public health and restricts the developments of economy and society, and brings it into the national research projects. The threat and challenge from AD has drawn the high attention of the scientific and AD now has become the hot scientific problem attracted multidiscipline to unite and tackle it.Although Alzheimer clarified the two pathological characteristics of AD in 1906, that is, extracellular senile plaques and intracellular neurofibrillary tangles in the brain, until the mid 1980s, with the discovery of the major components of the senile plaques, i.e., amyloid-βpeptide (Aβ), the study of the molecular mechanisms of AD reached a new rapidly developing era. The study in the most recently decade indicates that the aggregation of Aβand the generation of reactive oxygen species within the neocortex, may be closely related to metal-Aβinteractions. The study of the mechanisms of metal-Aβinteractions has made increasingly rapid progress, and has become one of the mainstream research fields of the molecular mechanism of AD.A series of intensive studies of the metal-Aβinteractions, especially Zn(II), Cu(II)with Aβ, has been made by a range of complementary spectroscopies, such as EPR spectroscopy, NMR, Raman spectroscopy, CD, as well as potentiometric curves, aggregation assays, and competitive metal capture analysis techniques. Aggregation of Aβinto fibrils is a key pathological event in AD. There is now compelling evidence that Aβdoes not spontaneously aggregate, but that there is an age-dependent reaction with excess brain metal (copper, iron, and zinc), which induces Aβto precipitate into metal-enriched masses (plaques).Based on a large body of experimental data, the main work in this dissertation which was carried out by molecular modeling method including the molecular mechanics method and molecular dynamics simulation is summarized as follows.1 Molecular mechanics study of the inhibitory mechanism of Cu(II) on the aggregation of Aβ. At nearly physiological concentrations, Zn(II) rapidly precipitate soluble Aβinto amyloid aggregates in vitro. Different from Zn(II) in a wide pH range (>6.0), Cu(II) induce Aβaggregating only at mildly acidic pH which represents physiological acidosis, and yet strong inhibit Aβfrom aggregation at neutral and basic pH. Furthermore, Cu(II) compete with Zn(II) and inhibit the Zn(II)-induced aggregation of Aβ. So Cu(II) appeal to many researchers for its potential of being an inhibitor on the aggregation of Aβin vivo. It is reported that in severely degenerated brain regions of AD patients such as the amygdala and hippocampus, the concentration of Cu(II) is significantly decreased compared to age-matched controls, however, Zn(II) still remains at comparatively high concentrations. These observations suggest that the effective inhibition of Cu(II) on the Zn(II)-induced aggregation of Aβmay be severely weakened by the decrease of Cu(II) concentrations and result in the excessive deposition of Aβand the degeneration of the brain.The possible mechanism of the inhibitory effect of Cu(II) is investigated for the first time by molecular modeling method. In the mono-ring mode, the Y10 residue promotes typical quasi-helix conformations of Aβ. Specially, [Cu-H13(Nπ)-Y10(OH)] complex forms a local 3.010 helix conformation. In the multi-ring mode, the side chains of Q15 and E11 residues collaborate harmoniously with other chelating ligands producing markedly low energies and quasi-helix conformations. [Cu-3N-Q15(O)-E11(O1)] and [Cu-H13(Nπ)-Y10(OH)] complex with quasi-helix conformations may prefer soluble forms in solution. In addition, hydrogen-bond interactions may be the main driving force for Aβaggregation. All the results will provide helpful clues for an improved understanding of the role of Cu(II) in the pathogenesis of AD and contribute to the development of an 'anti-amyloid' therapeutic strategy. 2 Molecular dynamics simulations of the coordination mechanism of Cu(II) with amyloidβ-peptide. A growing body of evidence indicates that the formation of soluble Cu(II)-Aβcomplexes is the key link of Cu(II) strongly inhibiting the aggregation of Aβunder certain conditions. The coordination of Cu(II) with Aβmakes the conformation of Aβtransit markedly, and forms the stable Cu(II)-Aβcomplexes with soluble conformations, thus achieves the inhibition on the aggregation of Aβ. So it is meaningful to investigate the dynamics behavior of the coordination of Cu(II) with Aβand the mechanism of conformational transition for improving the understanding of the properties of Aβ, the effect of metal ions on the conformational transition and the aggregation of Aβ. Unfortunately, because of the fibril's extreme insolubility and the monomer's high propensity to aggregate, investigation of the dynamics behavior of soluble Cu(II)-Aβcomplexes in the atomic detail by means of experimental methods is still intractable. In present work, computational simulation with its extremely high time resolution and atomic level representation was used in elucidating the effect of metal ions on the conformational transition and the aggregation of Aβ.By molecular dynamics simulations, we have explored the dynamics behavior of the coordination of Cu(II) with Aβand the mechanism of the conformational conversion of Aβ, and constructed the Q function method based on the radial distribution function analysis to evaluate the coordination of atoms in polydentated flexible ligands, such as Aβ. Also, the detailed process of how the metal coordination shell is constructed is illustrated, and the binding mechanism of Cu(II)-Aβsoluble complexes is illuminated on atomic level. Furthermore, certain dynamics characteristics of the coordination of Cu(II) with Aβ, that is, the coordination competitive effect of the atoms in the backbone of Aβ, the coordination repulsive effect of the atoms in the side-chain of Aβ, and the template effect of Cu(II), are elucidated. From the analysis of the trajectory data, we find that the metal template effect which results from the rigidity of the metal coordination geomtry, and the coordination repulsive effect of the atoms which results from the rigid geometry unit, are the important factors influencing whether the atoms can coordinate with Cu(II) and the coordination priority. By the conformational analysis, we find the conformational saltation phenomenon of Cu(II)-Ap soluble complexes, which is driven by the cooperation of the water-bridged coordination bond- hydrogen bond. The above results lay the theoretical foundation for the deeply understanding of the inhibitory effect of Cu(II) on the aggregation of Aβ, and will provide helpful clues for elucidating the relation of the metabolism imbalance of metal ions with the pathogenesis of AD and the metal-Aβinteraction- based drug design.3 Molecular modeling of the ion channel-like nanotube structure of amyloidβ-peptide. The ion channel hypothesis of AD proposes that Aβconverts its conformations and assembles into ion channel-like structures, which insert into plasma membranes and may lead to the leakage of membrane and the disruption of calcium homeostasis, and eventually result in the damage or death of neurons. Although a growing body of evidence supports the ion channel hypothesis, the high resolution structure of Aβchannel still remains unclear experimentally. Based on the experimental data, the structure models of Aβchannel can be constructed by theoretical methods, which provides a alternative approach to insight into the formation of Aβchannel and its ion permeation mechanism.The nanotube structural model of Aβchannel was frist built by molecular modeling method in this work. The results reveal that the hydrogen bond net is one of the key factors to stabilize the structure. The hydrophobicity distribution mode of the side chains is in favor of the structure inserting into the bilayers and forming a hydrophilic pore. The lumen space is under the control of the negative potential, weaker but spreading continuously, to which the cation selectivity attributes; meanwhile, the alternate distribution of the stronger positive and negative potentials makes the electrostatic distribution of the structure framework balance, which is also one of the key factors stabilizing the structure. In addition, we found that after Zn(II) entering the negative-potential-controlled pore of the tubular structure, it can form stable chelate-ring by coordinating with the imidazole nitrogen atoms of the H13 residue and the carboxyl oxygen atoms of the E11 residue, which all have higher affinity with Zn(II). In this way, the Zn(II) chelated with the pore occupies part of the pore space itself; on the other hand, the positive charges carried by the Zn(II) electrostatically repulse the successive entering of other cations into the pore, so the pore is jammed and the permeation of the channel is blocked off. This result is consistent with the experimentally found blockage effect of Zn(II) on the A|3 channels. The results lay the theoretical foundation for illuminating the structure stability and the ion selectivity and permeability, and give a clue to elucidating the molecular mechanism of AD and designing novel drugs for preventing or reversing AD at the root.With the increasingly rapid progress of the molecular mechanisms of AD and many new therapies directly targeting the mechanisms underlying AD are now in the pipeline, we are entering a new dawn that promises the delivery of revolutionary developments for the control of dementias. We hope that by ceaseless exertions humans could overwhelm AD eventually.
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