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: 8271740
• 负责人: Louis Noodleman
• 金额: $ 36.38万
• 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 2016-02-29
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8271740
• 关键词: Active Sites; Aerobic Bacteria; Aging; Binding; Cell membrane; Chemicals; Complex; Computer Simulation; Defect; Detection; Electron Transport; Electronics; Electrons; Electrostatics; Environment; Enzymes; Fees; Future; Goals; Health; Heme; Hereditary Disease; Human; Hydrogen Peroxide; Hydroxyl Radical; Kinetics; Lead; Link; Malignant Neoplasms; Membrane; Membrane Proteins; Metabolic; Metabolic Diseases; Metabolism; Methodology; Methods; Mitochondria; Modeling; Molecular; Molecular Machines; Mutagenesis; Nature; Optics; Oxidation-Reduction; Oxygen; Pathology; Pathway interactions; Play; Process; Production; Property; Proton Pump; Proton-Motive Force; Protons; Quantum Mechanics; Reaction; Reactive Oxygen Species; Resolution; Roentgen Rays; Role; Solvents; Spectrum Analysis; Structure; Superoxides; System; Testing; Thermus thermophilus; Transition Elements; Work; aqueous; base; chemical bond; cytochrome c oxidase; density; electronic structure; improved; insight; metal complex; molecular dynamics; molecular mechanics; phenolate; physical model; quantum; quantum chemistry; research study; tautomer; theories

DESCRIPTION (provided by applicant): 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 in B-type cytochrome c oxidases, comparing also to A-type cytochrome c oxidases (CcO's). Aim 1. To develop a quantum/electrostatic model explaining how chemical bonding and proton/electron flow to molecular oxygen within the Fe-Cu dinuclear complex (DNC) leads to proton pumping across the membrane. QM/MM/MD studies will provide insights into dynamic processes of proton transfer within and the proton exit channel from the DNC. Aim 2. Detection and characterization of peroxo bridged Fe-Cu species will be related to corresponding electronic states from DFT. DFT calculations of vibrational spectra and other electronic properties (Mossbauer and optical) will be performed for comparisons with experimental spectroscopies. Aim 3. The K-pathway for proton transfer into the dinuclear Fe-Cu complex will be analyzed using DFT/electrostatics and QM/MM/MD methods. Aim 4. We will further develop current methodologies to improve the quality of 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. Cytochrome c oxidase (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. PUBLIC HEALTH RELEVANCE: We are using methods from quantum chemistry, electrostatics, and molecular dynamics to obtain a detailed mechanistic understanding of how oxygen binding and electron/proton flow into cytochrome c oxidase leads to proton pumping across the inner membrane of mitochondria in humans, and similarly across the plasma membrane in most aerobic bacteria. The proton motive force generated is used for ATP production, and defects in this enzyme harm energy production, and also can generate reactive radical oxygen species. Defects in mitochondrial metabolism are associated with many metabolic diseases, cancers, and pathologies of aging, so analyzing this molecular machine has great significance.

描述（由申请人提供）：拟开展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B型细胞色素c氧化酶催化反应途径的详细机制理解，并与A型细胞色素进行比较 c氧化酶（CcO）。目标 1. 开发量子/静电模型，解释 Fe-Cu 双核络合物 (DNC) 内的化学键合和质子/电子流向分子氧如何导致质子泵送穿过膜。 QM/MM/MD 研究将深入了解 DNC 内质子转移和质子退出通道的动态过程。目标 2. 过氧桥联 Fe-Cu 物质的检测和表征将与 DFT 中相应的电子态相关。将进行振动光谱和其他电子特性（穆斯堡尔和光学）的 DFT 计算，以便与实验光谱进行比较。目标 3. 将使用 DFT/静电和 QM/MM/MD 方法分析质子转移到双核 Fe-Cu 络合物的 K 路径。目标 4. 我们将进一步开发当前的方法，以提高这些大型活性位点模型的 DFT 计算质量，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。线粒体的细胞色素 c 氧化酶（复合体 IV）将通过电子传递链的电子传递与穿过线粒体内膜的质子泵送联系起来，类似地，在大多数需氧细菌中也将质子泵送穿过质膜。这是用于 ATP 生产的质子动力。线粒体 CcO 在人类健康中发挥着重要作用，因为最重要的代谢功能需要充足的 ATP 供应。此外，电子或质子转移反应或 CcO 上氧结合的破坏可能导致产生破坏性的活性氧物质，包括羟基和超氧自由基以及过氧化氢。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非常重要，并且也与衰老病理学相关。 公共健康相关性：我们正在使用量子化学、静电学和分子动力学方法来详细了解氧结合和电子/质子流入细胞色素c氧化酶如何导致质子泵送穿过人类线粒体内膜，以及类似地穿过大多数需氧细菌的质膜。产生的质子动力用于ATP的产生，这种酶的缺陷会损害能量的产生，并且还会产生活性自由基氧。线粒体代谢缺陷与许多代谢疾病、癌症和衰老病理有关，因此分析这种分子机器具有重要意义。