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MODELLING MOLECULAR STABILITY IN GAMMA B CRYSTALLIN

机译:模拟GAMMA B晶体中的分子稳定性

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Molecular modelling and dynamics simulations of γB crystallin and a number of its adducts were used to simulate effects of post-translational modifications. N-terminal modifications which disrupted the surface charge network of γ-crystallin did not produce significant unfolding in any part of the γ-crystallin molecule (P > 0.05) consistent with the results of in vitro aggregation studies. There were no significant changes to the molecular volume of the protein, suggesting that adduct formation did not result in molten globule formation. Adduct formation did however increase the vulnerability of particular γ-crystallin cysteine residues to sulphydryl bond formation and so increased the possibility of mixed disulphide formation with glutathione. Modelling of such secondary modification products (containing both N-terminal modifications and glutathione adducts) demonstrated significant (P < 0.05) structural changes. This suggests that a post-translational modification pathway leading to crystallin cross-linking and cataractogenesis proceeds via a number of co-operative steps involving both modification at the N-terminus and mixed glutathione formation.
机译:γB晶状蛋白及其许多加合物的分子建模和动力学模拟被用来模拟翻译后修饰的作用。与体外凝集研究结果一致,破坏γ-晶状蛋白蛋白表面电荷网络的N末端修饰在γ-晶状蛋白蛋白分子的任何部分均未产生明显的折叠(P> 0.05)。蛋白质的分子体积没有明显变化,表明加合物的形成不会导致熔融小球的形成。然而,加合物的形成确实增加了特定的γ-结晶蛋白半胱氨酸残基对巯基键形成的脆弱性,因此增加了与谷胱甘肽混合形成二硫化物的可能性。此类二级修饰产物(同时包含N末端修饰和谷胱甘肽加合物)的建模显示出显着(P <0.05)的结构变化。这表明导致结晶蛋白交联和白内障发生的翻译后修饰途径是通过许多合作步骤进行的,这些步骤既涉及N末端的修饰又包括混合谷胱甘肽的形成。

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