Quantum Chemistry of Proton Pumping by Cytochrome c Oxidases

细胞色素 c 氧化酶质子泵浦的量子化学

• 批准号: 9238520
• 负责人: Louis Noodleman
• 金额: $ 41.22万
• 依托单位: SCRIPPS RESEARCH INSTITUTE, THE
• 依托单位国家: 美国
• 财政年份: 2012
• 资助国家: 美国
• 起止时间: 2012-04-01 至 2020-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9238520
• 关键词: Active Sites; Address; Aerobic Bacteria; Aging; Binding; Cell membrane; Charge; Chemicals; Chemistry; Collaborations; Complex; Computer Simulation; Crystallization; Cytochrome c Group; Data; Defect; Detection; Development; Electron Transport; Electrons; Electrostatics; Environment; Enzymes; Geometry; Goals; Health; Heme; Hereditary Disease; Human; Hydrogen Peroxide; Hydroxyl Radical; Kinetics; Lead; Link; Lipids; Malignant Neoplasms; Mechanics; Membrane; Membrane Proteins; Metabolic; Metabolic Diseases; Methodology; Methods; Mitochondria; Modeling; Molecular; Molecular Analysis; Molecular Machines; Monitor; Mutation; Nature; Nuclear; Oxidases; Oxidation-Reduction; Oxides; Oxygen; Pathology; Pathway interactions; Phase; Physiological; Play; Process; Production; Property; Proton Pump; Proton-Motive Force; Protons; Quantum Mechanics; Radiation induced damage; Reaction; Reactive Oxygen Species; Resolution; Roentgen Rays; Role; Site; Solvents; Spectrum Analysis; Structure; Superoxides; Testing; Theoretical model; Thermus thermophilus; Water; Work; X ray diffraction analysis; X-Ray Diffraction; aqueous; base; chemical bond; complex IV; cytochrome c oxidase; density; electronic structure; experimental study; geometric structure; heme a; improved; insight; metal complex; mitochondrial metabolism; molecular dynamics; molecular mechanics; mutant; oxidation; protonation; quantum; quantum chemistry; simulation; synchrotron radiation; theories; tool; uptake; vibration

The proposed work involves density functional theory (DFT) calculations of geometric and electronic structure, electrostatics calculations, and quantum-mechanics/molecular-mechanics/molecular-dynamics (QM/MM/MD) simulations to provide a detailed mechanistic understanding of the catalytic reaction pathways and mechanisms of proton pumping in B-type and A-type cytochrome c oxidases (CcO's). Aim 1. Develop a quantum/electrostatic model explaining how chemical bonding and proton/electron flow to molecular oxygen within the Fea3-CuB dinuclear complex (DNC) leads to proton pumping across the membrane. QM/MM/MD studies will provide insights into dynamic processes of proton uptake, proton transfer within the DNC and the proton exit channel from the DNC. Aim 2. Detection and characterization of various oxygen species between and/or bridging the Fe-Cu species will be related to corresponding electronic states from DFT. Calculations of vibrational spectra and other electronic properties (Mössbauer) will be performed to connect our hypotheses with experimental spectroscopies. Aim 3. New single crystal X-ray structures at high resolution with little radiation damage will be obtained for B- type CcO from Thermus thermophilus. These will be analyzed in comparison to other structures and DFT calculations. Aim 4. We will further develop current methodologies to improve the quality of quantum chemical DFT calculations for these large active site models, to analyze dynamic processes with QM/MM/MD, and for the physical description of the remaining protein/membrane/aqueous solvent environment. CcO (Complex IV) of mitochondria links electron transfer through the electron transport chain to proton pumping across the inner membrane of the mitochondria, and similarly, across the plasma membrane in most aerobic bacteria. This is the proton motive force utilized for ATP production. Mitochondrial CcO's play an essential role in human health because adequate ATP supplies are required for most important metabolic functions. Also, disruptions in electron or proton transfer reactions or oxygen binding at CcO can lead the production of damaging reactive oxygen species including hydroxyl and superoxide radicals, and hydrogen peroxide. Understanding the structures, mechanisms, and functions of mitochondrial CcO's is important for better analysis of many genetic and metabolic diseases and cancers, and is also relevant to pathologies of aging.

拟议的工作涉及几何和电子结构的密度泛函理论（DFT）计算， 静电计算，以及量子力学/分子力学/分子动力学（QM/MM/MD） 模拟以提供对催化反应途径的详细机制理解 B 型和 A 型细胞色素 c 氧化酶 (CcO) 中的质子泵机制。 目标 1. 开发一个量子/静电模型来解释化学键合和质子/电子如何流动到 Fea3-CuB 双核络合物 (DNC) 内的分子氧导致质子泵送穿过 膜。 QM/MM/MD 研究将深入了解质子吸收、质子转移的动态过程 在 DNC 内和 DNC 的质子出口通道内。 目标 2. 检测和表征 Fe-Cu 物质之间和/或桥接 Fe-Cu 物质之间的各种氧物质 将与 DFT 中相应的电子态相关。振动谱和其他的计算 将进行电子特性（穆斯堡尔）以将我们的假设与实验联系起来 光谱检查。 目标 3. 获得 B- 辐射损伤小、高分辨率的新单晶 X 射线结构 来自嗜热栖热菌的 CcO 型。这些将与其他结构和 DFT 进行比较分析 计算。 目标 4. 我们将进一步发展现有的方法来提高量子化学 DFT 的质量 对这些大型活性位点模型进行计算，以使用 QM/MM/MD 分析动态过程， 以及剩余蛋白质/膜/水溶剂环境的物理描述。 线粒体的 CcO（复合体 IV）通过电子传递链将电子传递连接到质子 泵送穿过线粒体内膜，类似地，在大多数细胞中泵送穿过质膜 需氧细菌。这是用于 ATP 生产的质子动力。线粒体 CcO 的作用 对人类健康至关重要，因为最重要的代谢需要充足的 ATP 供应 功能。此外，电子或质子转移反应或 CcO 上氧结合的破坏也会导致 产生破坏性的活性氧，包括羟基和超氧自由基以及氢气 过氧化物。了解线粒体 CcO 的结构、机制和功能对于 更好地分析许多遗传和代谢疾病以及癌症，并且也与病理学相关 老化。