Molecular Mechanisms of Energy Conversion in Respiratory Complex I

呼吸复合物 I 能量转换的分子机制

• 批准号: 277706513
• 负责人: Professor Dr. Ville Kaila
• 金额: --
• 依托单位: Stockholm University
• 依托单位国家: 德国
• 项目类别: Research Grants
• 财政年份: 2015
• 资助国家: 德国
• 起止时间: 2014-12-31 至 2019-12-31
• 项目状态: 已结题
• 来源: https://gepris.dfg.de/gepris/projekt/277706513?language=en
• 关键词: Molecular; Mechanisms; Energy; Conversion; Respiratory

Elucidating molecular mechanisms of biological energy conversion is crucial both for understanding the biochemistry of the cell and for developing new biomimetic energy technologies. Complex I (NADH:ubiquinone-oxidoreductase) functions as an initial entry point for electrons in the respiratory chains of bacteria and eukaryotes. By reducing quinones (Q) in its soluble domain, Complex I couples the free energy released in the process to the translocation of protons in its membrane domain. The proton transfer across the inner mitochondrial membrane and cytoplasmic membrane of bacteria generates an electrochemical proton gradient, which is subsequently used for synthesis of ATP by FoF1-ATPase and for active transport. Remarkably, mutation of titratable residues ~200 Å away from the site of Q-reduction in Complex I, inhibits both the proton-pumping and Q reduction. Although this is thermodynamically expected for a reversible proton-coupled electron transfer (PCET) machinery, it imposes several restrictions on the coupling mechanism. To explain the principles of this long-range energy propagation in Complex I, both direct (redox-driven) and indirect (conformationally-driven) mechanisms have been suggested, but the molecular details remains elusive. In this project, we employ a broad range of state-of-the-art quantum and classical molecular simulation techniques to study molecular mechanisms of the long-range proton-coupled electron transfer catalyzed by Complex I. The computational approaches provide powerful methodologies to probe mechanistic hypothesis of complex biochemical systems, and thus to get insight in the catalytic mechanisms on a molecular level. Our molecular simulations aim to address the structure, dynamics and energetics of key catalytic steps in Complex I, thus providing complementary, but also inaccessible information to many experimental techniques. In this project we aim to elucidate (1) the energetics and dynamics of the proton transfer process in the antiporter-like membrane domain of Complex I, (2) the energetics of the electron transfer process that lead to reduction of quinones in the soluble domain of Complex I, and (3) how the redox-induced changes at the quinone site are responsible for activating the proton pump.

阐明生物能量转化的分子机制对于理解细胞的生物化学和开发新的仿生能源技术都是至关重要的。复合体I （NADH：泛素氧化还原酶）是细菌和真核生物呼吸链中电子的初始入口点。配合物I通过在其可溶结构域中还原醌(Q)，将过程中释放的自由能与膜结构域中质子的易位偶联。质子在细菌线粒体内膜和细胞质膜上的转移产生电化学质子梯度，随后由fof1 -ATP酶合成ATP并进行主动转运。值得注意的是，络合物I中距离Q还原位点~200 Å的可滴定残基突变抑制了质子泵送和Q还原。尽管这是可逆质子耦合电子转移（PCET）机制的热力学预期，但它对耦合机制施加了一些限制。为了解释络合物I中这种远程能量传播的原理，已经提出了直接（氧化还原驱动）和间接（构象驱动）机制，但分子细节仍然难以捉摸。在这个项目中，我们采用了广泛的最先进的量子和经典分子模拟技术来研究络合物i催化的远距离质子耦合电子转移的分子机制。计算方法为探索复杂生化系统的机制假设提供了强有力的方法，从而在分子水平上深入了解催化机制。我们的分子模拟旨在解决复合体I中关键催化步骤的结构，动力学和能量学，从而为许多实验技术提供补充但也无法获得的信息。在这个项目中，我们的目标是阐明(1)在络合物I的反转运体膜结构域中质子转移过程的能量学和动力学，(2)在络合物I的可溶性结构域中导致醌还原的电子转移过程的能量学，以及(3)氧化还原诱导的醌位点的变化是如何激活质子泵的。

项目成果

Trendbericht Theoretische Chemie: Molekulare Mechanismen der biologischen Energieumwandlung

趋势报告理论化学：生物能量转换的分子机制

• DOI: 10.1002/nadc.20194092115
• 发表时间: 2019
• 期刊: Nachrichten aus der Chemie
• 作者: Kaila VRI

Chapter 4:Multi-scale Molecular Simulations on Respiratory Complex I

第 4 章：呼吸复合物 I 的多尺度分子模拟

• DOI: 10.1039/9781788010405-00081
• 发表时间: 2018
• 作者: Kaila VRI

How inter-subunit contacts in the membrane domain of complex I affect proton transfer energetics.

• DOI: 10.1016/j.bbabio.2018.06.001
• 发表时间: 2018-09
• 期刊: Biochimica et biophysica acta. Bioenergetics
• 作者: Di Luca A;Mühlbauer ME;Saura P;Kaila VRI
• 通讯作者: Kaila VRI

How cardiolipin modulates the dynamics of respiratory complex I

• DOI: 10.1126/sciadv.aav1850
• 发表时间: 2019-03-01
• 期刊: SCIENCE ADVANCES
• 影响因子: 13.6
• 作者: Jussupow, Alexander;Di Luca, Andrea;Kaila, Ville R., I
• 通讯作者: Kaila, Ville R., I

Redox-induced activation of the proton pump in the respiratory complex I

氧化还原诱导的呼吸复合物 I 中质子泵的激活

• DOI: 10.1073/pnas.1503761112
• 发表时间: 2015
• 期刊: Proceedings of the National Academy of Sciences
• 作者: Sharma V;Belevich G;Gamiz-Hernandez AP;Vattulainen I;Wikström M;Hummer G;Kaila VRI
• 通讯作者: Kaila VRI