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首页> 外文学位 >Conformational Transition Pathways in Signaling and Enzyme Catalysis Explored by Computational Methods.
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Conformational Transition Pathways in Signaling and Enzyme Catalysis Explored by Computational Methods.

机译：计算方法探讨了信号传导和酶催化的构象转变途径。

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摘要

Biomolecules are dynamic in nature and visit a number of states while performing their biological function. However, understanding how they interconvert between functional substates is a challenging task. In this thesis, we employ enhanced computational strategies to reveal in atomistic resolution transition states and molecular mechanism along conformational pathways of the signaling protein Nitrogen Regulatory Protein C (NtrC) and the enzyme Adenylate Kinase (Adk).;Targeted Molecular Dynamics (TMD) simulations and NMR experiments have previously found the active/inactive interconversion of NtrC is stabilized by non-native transient contacts. To find where along the conformational pathway they lie and probe the existence of multiple intermediates, a beyond 8mus-extensive mapping of the conformational landscape was performed by a multitude of straightforward MD simulations relaxed from the biased TMD pathway. A number of metastable states stabilized by local interactions was found to underline the conformational pathway of NtrC. Two spontaneous transitions of the last stage of the active-to-inactive conversion were identified and used in path sampling procedures to generate an ensemble of truly dynamic reactive pathways. The transition state ensemble (TSE) and mechanistic descriptors of this transition were revealed in atomic detail and verified by committor analysis.;By analyzing how pressure affects the dynamics and function of two homologous Adk proteins - the P.Profundum Adk surviving at 700atm pressure in the deep sea, and the E. coli Adk that lives at ambient pressures - we indirectly obtained atomic information about the TSE of the large-amplitude rate-limiting conformational opening of the Adk lids. Guided by NMR experiments showing significantly decreased activation volumes of the piezophile compared to its mesophilic counterpart, TMD simulations revealed the formation of an extended hydrogen-bonded water network in the transition state of the piezophile that can explain the experimentally measured activation volume differences. The transition state of the conformational change was proposed to lie close to the closed state. Additionally, a number of descriptors were used to characterize the free energy landscape of the mesophile. It was found that the features of landscape are highly sensitive to the binding of different ligands, their protonation states and the presence of magnesium.
机译：生物分子本质上是动态的，在执行其生物学功能时会进入许多状态。但是，了解它们如何在功能子状态之间相互转换是一项艰巨的任务。在本文中，我们采用了增强的计算策略，以揭示信号传导蛋白氮调节蛋白C（NtrC）和腺苷酸激酶（Adk）构象途径在原子分辨率下的过渡态和分子机制。目标分子动力学（TMD）模拟NMR实验以前已经发现NtrC的主动/非主动互变可以通过非自然瞬态接触来稳定。为了找到它们沿着构象路径的位置并探究多种中间体的存在，通过从偏向TMD路径放松的大量简单的MD模拟，对构象景观进行了超过8mus的广泛映射。发现许多通过局部相互作用稳定的亚稳态强调了NtrC的构象途径。识别了主动到非主动转换的最后阶段的两个自发转变，并在路径采样过程中使用它们来生成真正的动态反应路径集合。过渡状态集合（TSE）和此过渡的机制描述子在原子细节中得到了揭示并通过提交者分析进行了验证。通过分析压力如何影响两种同源Adk蛋白的动力学和功能-在温度为700atm的大气压下存活的P.Profundum Adk。深海和生活在环境压力下的大肠杆菌Adk-我们间接获得了有关Adk盖的大幅度限速构象开口的TSE的原子信息。在核磁共振实验的指导下，嗜中性亲虫的活化体积比中温对应物显着降低，TMD模拟显示在亲核性过渡态中形成了扩展的氢键水网络，这可以解释实验测得的活化体积差异。构象变化的过渡态被提出为接近闭合态。另外，许多描述符用于表征嗜温菌的自由能态。发现景观的特征对不同配体的结合，其质子化状态和镁的存在高度敏感。

著录项

  • 作者

    Pachov, Dimitar V.;

  • 作者单位

    Brandeis University.;

  • 授予单位 Brandeis University.;
  • 学科 Molecular physics.;Biochemistry.;Systematic biology.;Condensed matter physics.
  • 学位 Ph.D.
  • 年度 2010
  • 页码 246 p.
  • 总页数 246
  • 原文格式 PDF
  • 正文语种 eng
  • 中图分类
  • 关键词

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