Amyloid 尾-Peptide 25鈥?5 Self-Assembly and Its Inhibition: A Model Undecapeptide System to Gain Atomistic and Secondary Structure Details of the Alzheimer鈥檚 Disease Process and Treatment
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- 作者：Marina Naldi ; Jessica Fiori ; Marco Pistolozzi ; Alex F. Drake ; Carlo Bertucci ; Rongliang Wu ; Krzysztof Mlynarczyk ; Slawomir Filipek ; Angela De Simone ; Vincenza Andrisano
- 刊名：ACS Chemical Neuroscience
- 出版年：2012
- 出版时间：November 21, 2012
- 年：2012
- 卷：3
- 期：11
- 页码：952-962
- 全文大小：388K
- 年卷期：v.3,no.11(November 21, 2012)
- ISSN：1948-7193
文摘
Combined results of theoretical molecular dynamic simulations and in vitro spectroscopic (circular dichroism and fluorescence) studies are presented, providing the atomistic and secondary structure details of the process by which a selected small molecule may destabilize the 尾-sheet ordered 鈥渁myloid鈥?oligomers formed by the model undecapeptide of amyloid 尾-peptide 25鈥?5 [A尾(25鈥?5)]. A尾(25鈥?5) was chosen because it is the shortest fragment capable of forming large 尾-sheet fibrils and retaining the toxicity of the full length A尾(1鈥?0/42) peptides. The conformational transition, that leads to the formation of 尾-sheet fibrils from soluble unordered structures, was found to depend on the environmental conditions, whereas the presence of myricetin destabilizes the self-assembly and antagonizes this conformational shift. In parallel, we analyzed several molecular dynamics trajectories describing the evolution of five monomer fragments, without inhibitor as well as in the presence of myricetin. Other well-known inhibitors (curcumin and (鈭?-tetracycline), found to be stronger and weaker A尾(1鈥?2) aggregation inhibitors, respectively, were also studied. The combined in vitro and theoretical studies of the A尾(25鈥?5) self-assembly and its inhibition contribute to understanding the mechanism of action of well-known inhibitors and the peptide amino acid residues involved in the interaction leading to a rational drug design of more potent new molecules able to antagonize the self-assembly process.