通过氧化 CH 链和 CL 链之间的二硫键,对抗体-磷脂识别进行异构控制。

Protein Engineering, Design and Selection Pub Date : 2017-01-01 Epub Date: 2016-11-29 DOI:10.1093/protein/gzw065
Jun Zhao, Ruth Nussinov, Buyong Ma
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引用次数: 0

摘要

人们对无序抗原的同源抗体识别无序抗原的分子细节还没有像折叠蛋白抗原那样进行广泛的研究,而且还有许多未知。为了跟踪抗体的构象变化以及抗体亚基之间和抗体与抗原之间的相互作用,我们对Fab和朊病毒相关肽的复合物进行了分子动力学(MD)模拟。我们观察到,恒定结构域中的链间二硫键限制了Fab的构象变化,尤其是CH1结构域中的环,从而抑制了Fab亚结构域之间的交叉作用,进而阻止了朊病毒肽的结合。我们进一步确定了肽与 Fab 常域之间的几种负相关和正相关运动,这表明常域与抗原之间存在结构上的交叉对话。这种交叉作用受到链间二硫键的影响,二硫键减少了它们之间的路径数量。重要的是,对复合物及其结合的水分子进行的网络分析发现,这些水分子构成了 Fab/肽复合物网络和潜在异构途径的组成部分。目前的工作重点是制定策略,将这些新的网络通信(包括相关的水分子)纳入抗体设计的巨大挑战中。
本文章由计算机程序翻译,如有差异,请以英文原文为准。
Allosteric control of antibody-prion recognition through oxidation of a disulfide bond between the CH and CL chains.

Molecular details of the recognition of disordered antigens by their cognate antibodies have not been studied as extensively as folded protein antigens and much is still unknown. To follow the conformational changes in the antibody and cross-talk between its subunits and with antigens, we performed molecular dynamics (MD) simulations of the complex of Fab and prion-associated peptide in the apo and bound forms. We observed that the inter-chain disulfide bond in constant domains restrains the conformational changes of Fab, especially the loops in the CH1 domain, resulting in inhibition of the cross-talk between Fab subdomains that thereby may prevent prion peptide binding. We further identified several negative and positive correlations of motions between the peptide and Fab constant domains, which suggested structural cross-talks between the constant domains and the antigen. The cross-talk was influenced by the inter-chain disulfide bond, which reduced the number of paths between them. Importantly, network analysis of the complex and its bound water molecules observed that those water molecules form an integral part of the Fab/peptide complex network and potential allosteric pathways. On-going work focuses on developing strategies aimed to incorporate these new network communications-including the associated water molecules-toward the grand challenge of antibody design.

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