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

基本信息

批准号：
8819552
负责人：
Louis Noodleman
金额：
$ 34.15万
依托单位：
SCRIPPS RESEARCH INSTITUTE, THE
依托单位国家：
美国
项目类别：
财政年份：
2012
资助国家：
美国
起止时间：
2012-04-01 至 2016-12-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8819552
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 geometric structure improved insight metal complex molecular dynamics molecular mechanics phenolate physical model quantum quantum chemistry research study tautomer theories

项目摘要

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.

描述（由申请人提供）：拟议的工作涉及几何和电子结构的密度泛函理论（DFT）计算、静电学计算以及量子力学\分子力学\分子动力学（QM/MM/MD）模拟，以提供详细的机理理解B 型细胞色素 c 氧化酶的催化反应途径，也与 A 型细胞色素 c 氧化酶 (CcO) 进行比较。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/静电学和 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。