纤原胰岛素与蛋白质的相互作用:分子对接研究

V. Trusova, O. Zhytniakivska, U. Tarabara, Kateryna Vus, G. Gorbenko
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摘要

在过去的几十年里,越来越多的注意力集中在确定对特定蛋白质聚集体、淀粉样原纤维的潜在毒性负责的因素上,淀粉样原纤维的形成与一系列人类病理有关,包括神经退行性疾病、系统性淀粉样变性、II型糖尿病等。尽管在阐明淀粉样蛋白原纤维的细胞毒性作用机制方面取得了重大进展,但原纤维-蛋白相互作用在决定淀粉样蛋白毒性中的作用仍然知之甚少。鉴于此,本研究采用分子对接技术研究胰岛素淀粉样原纤维(InsF)与天然球状状态下的血清白蛋白、溶菌酶和胰岛素三种重要的生物学多功能蛋白之间的相互作用。利用ClusPro, HDOCK, PatchDock和COCOMAPS web服务器,以及BIOVIA Discovery Studio软件,分析原纤维-蛋白质复合物的结构特征,如相互作用氨基酸残基的数量,原纤维和蛋白质界面残基的数量,各种相互作用的贡献,复合物形成时的隐藏面积等。结果表明:1)亲水性-亲水性和亲水性-疏水性相互作用在原纤维蛋白复合物的形成中起主导作用;Ii)所研究的蛋白质在纤维相互作用残基的数量上没有显著差异;Iii)主要的氢键形成残基为纤原胰岛素中的谷氨酰胺和天冬酰胺,血清白蛋白中的赖氨酸和溶菌酶中的精氨酸;蛋白与胰岛素原纤维络合时,极性埋埋面积大于非极性埋埋面积。获得了磷荧光染料TDV在原纤维-蛋白界面定位的分子对接证据。
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Interactions of Fibrillar Insulin with Proteins: A Molecular Docking Study
During the last decades growing attention has been paid to ascertaining the factors responsible for the toxic potential of particular protein aggregates, amyloid fibrils, whose formation is associated with a range of human pathologies, including the neurodegenerative diseases, systemic amyloidosis, type II diabetes, etc. Despite significant progress in elucidating the mechanisms of cytotoxic action of amyloid fibrils, the role of fibril-protein interactions in determining the amyloid toxicity remains poorly understood. In view of this, in the present study the molecular docking techniques has been employed to investigate the interactions between the insulin amyloid fibrils (InsF) and three biologically important multifunctional proteins, viz. serum albumin, lysozyme and insulin in their native globular state. Using the ClusPro, HDOCK, PatchDock and COCOMAPS web servers, along with BIOVIA Discovery Studio software, the structural characteristics of fibril-protein complexes such as the number of interacting amino acid residues, the amount of residues at fibril and protein interfaces, the contributions of various kinds of interactions, buried area upon the complex formation, etc. It was found that i) hydrophilic-hydrophilic and hydrophilic-hydrophobic interactions play dominating role in the formation of fibril-protein complexes; ii) there is no significant differences between the investigated proteins in the number of fibrillar interacting residues; iii) the dominating hydrogen bond forming residues are represented by glutamine and asparagine in fibrillar insulin, lysine in serum albumin and arginine in lysozyme; iv) polar buried area exceeds the nonpolar one upon the protein complexation with the insulin fibrils. The molecular docking evidence for the localization of phosphonium fluorescent dye TDV at the fibril-protein interface was obtained.
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