Mechanism of allosteric propagation across a β-sheet structure investigated by molecular dynamics simulations.
Mechanism of allosteric propagation across a β-sheet structure investigated by molecular dynamics simulations.
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DOI：
10.1002/prot.25050
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发表时间：
2016-07
影响因子：
2.9
通讯作者：
Thomas, Wendy E.
中科院分区：
文献类型：
--
作者：
Interlandi, Gianluca;Thomas, Wendy E.
关键词：
细菌粘附素FimH由变构调节的甘露糖结合凝集素结构域和共价连接的抑制性菌毛蛋白结构域组成。在正常条件下，两个结构域相互结合，并且FimH与甘露糖弱相互作用。然而，在张力下，结构域分离，凝集素结构域经历构象变化，从而加强其与甘露糖的键合。凝集素结构域的低和高亲和力状态的晶体学结构的比较揭示了主要在调节结构域间区域、甘露糖结合位点和连接两个远端区域的大β折叠中的构象变化。在这里，分子动力学模拟研究了构象变化如何在凝集素结构域的不同区域内和之间传播。发现结构域间区域向高亲和力构象移动，因为它变得更紧凑并在菌毛蛋白结构域分离后掩埋暴露的疏水表面。甘露糖结合位点在高亲和力状态下更刚性，这防止水渗透到口袋中。大的中央β折叠显示出软弹簧样扭曲。它的扭曲运动是适度相关的波动在监管和结合区，而弱相关性被认为是在这两个远端网站的直接比较。结果表明了所谓的“群体转移”模型，其中凝集素结构域与菌毛蛋白结构域或甘露糖的结合将β折叠锁定在相当扭曲或平坦的构象中，分别稳定低或高亲和力状态。Proteins 2016; 84：990-1008.版权所有2016作者.蛋白质：结构，功能和生物信息学出版的威利期刊，公司。
The bacterial adhesin FimH consists of an allosterically regulated mannose‐binding lectin domain and a covalently linked inhibitory pilin domain. Under normal conditions, the two domains are bound to each other, and FimH interacts weakly with mannose. However, under tensile force, the domains separate and the lectin domain undergoes conformational changes that strengthen its bond with mannose. Comparison of the crystallographic structures of the low and the high affinity state of the lectin domain reveals conformational changes mainly in the regulatory inter‐domain region, the mannose binding site and a large β sheet that connects the two distally located regions. Here, molecular dynamics simulations investigated how conformational changes are propagated within and between different regions of the lectin domain. It was found that the inter‐domain region moves towards the high affinity conformation as it becomes more compact and buries exposed hydrophobic surface after separation of the pilin domain. The mannose binding site was more rigid in the high affinity state, which prevented water penetration into the pocket. The large central β sheet demonstrated a soft spring‐like twisting. Its twisting motion was moderately correlated to fluctuations in both the regulatory and the binding region, whereas a weak correlation was seen in a direct comparison of these two distal sites. The results suggest a so called “population shift” model whereby binding of the lectin domain to either the pilin domain or mannose locks the β sheet in a rather twisted or flat conformation, stabilizing the low or the high affinity state, respectively. Proteins 2016; 84:990–1008. © 2016 The Authors. Proteins: Structure, Function, and Bioinformatics Published by Wiley Periodicals, Inc.
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