Reactive Center Loop Insertion in alpha-1-Antitrypsin Captured by Accelerated Molecular Dynamics Simulation

Andersen Ole Juul; Risor Michael Wulff; Poulsen Emil ChristianNielsen Niels Chr.Miao YinglongEnghild Jan J.Schiott Birgit

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Reactive Center Loop Insertion in alpha-1-Antitrypsin Captured by Accelerated Molecular Dynamics Simulation

机译：通过加速分子动力学模拟捕获的 α-1-抗胰蛋白酶中的反应性中心环插入

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Protease inhibition by metastable serine protease inhibitors (serpins) is mediated by one of the largest functional intradomain conformational changes known in biology. In this extensive structural rearrangement, protease-serpin complex formation triggers cleavage of the serpin reactive center loop (RCL), its subsequent insertion into central beta-sheet A, and covalent trapping of the target protease. In this study, we present the first detailed accelerated molecular dynamics simulation of the insertion of the fully cleaved RCL in alpha-1-antitrypsin (alpha(1)AT), the archetypal member of the family of human serpins. Our results reveal internal water pathways that allow the initial incorporation of side chains of RCL residues into the protein interior. We observed structural plasticity of the helix F (hF) element that blocks the RCL path in the native state, which is in excellent agreement with previous experimental reports. Furthermore, the simulation suggested a novel role of hF and the connected turn (thFs3A) as chaperones that support the insertion process by reducing the conformational space available to the RCL. Transient electrostatic interactions of RCL residues potentially fine-tune the serpin inhibitory activity. On the basis of our simulation, we generated the alpha(1)AT mutants K168E, E346K, and K168E/E346K and analyzed their inhibitory activity along with their intrinsic stability and heat-induced polymerization. Remarkably, the E346K mutation exhibited enhanced inhibitory activity along with an increased rate of premature structural collapse (polymerization), suggesting a significant role of E346 in the gatekeeping of the strain in the metastable native state.

机译：亚稳态丝氨酸蛋白酶抑制剂（丝氨酸蛋白酶抑制剂）对蛋白酶的抑制是由生物学中已知的最大功能性域内构象变化之一介导的。在这种广泛的结构重排中，蛋白酶-丝氨酸蛋白复合物的形成触发丝氨酸蛋白反应性中心环（RCL）的裂解，随后插入中心 β-折叠 A 中，以及靶蛋白酶的共价捕获。在这项研究中，我们首次展示了在人丝氨酸家族的原型成员 α-1-抗胰蛋白酶（alpha（1）AT）中插入完全裂解的 RCL 的详细加速分子动力学模拟。我们的研究结果揭示了允许RCL残基的侧链初始掺入蛋白质内部的内部水途径。我们观察到螺旋F（hF）元素的结构塑性，该元素在天然状态下阻断了RCL路径，这与之前的实验报告非常吻合。此外，仿真表明 hF 和连接匝（thFs3A）作为伴侣的新作用，通过减少 RCL 可用的构象空间来支持插入过程。RCL残基的瞬时静电相互作用可能会微调丝氨酸抑制活性。在模拟的基础上，我们生成了α（1）AT突变体K168E、E346K和K168E/E346K，并分析了它们的抑制活性以及它们的内在稳定性和热诱导聚合。值得注意的是，E346K突变表现出增强的抑制活性以及过早结构崩溃（聚合）速率的增加，表明E346在亚稳态天然状态下菌株的把关中起着重要作用。

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《Biochemistry》 |2017年第4期|634-646|共13页
作者
Andersen Ole Juul; Risor Michael Wulff; Poulsen Emil ChristianNielsen Niels Chr.Miao YinglongEnghild Jan J.Schiott Birgit;
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作者单位

Aarhus Univ, Ctr Insoluble Prot Struct InSPIN, Aarhus, Denmark;

Univ Calif San Diego, Howard Hughes Med Inst, La Jolla, CA 92093 USA;

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正文语种英语
中图分类生物化学;
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Reactive Center Loop Insertion in alpha-1-Antitrypsin Captured by Accelerated Molecular Dynamics Simulation

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