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）：拟议的工作涉及密度功能理论（DFT）的几何和电子结构，静电计算以及量子力学\分子力学\分子动力学（QM/MM/MM/MD）的计算，以提供对B-型Cycype cyto Chrome cyto Chrome cyto Chrome cyto Chrome cyto Chrome cyto Chrome的详细机械理解的模拟， C氧化酶（CCO）。目的1。开发量子/静电模型，以解释Fe-Cu Dinuclear复合物（DNC）内化学键和质子/电子流向分子氧的流量如何导致质子泵入整个膜。 QM/MM/MD研究将提供有关DNC内部质子转移和质子出口通道的动态过程的见解。 AIM 2。检测和表征过氧桥接的Fe-Cu物种将与DFT的相应电子状态有关。将对实验光谱法进行比较，对振动光谱和其他电子特性（Mossbauer和光学）进行DFT计算。 AIM 3。将使用DFT/静电和QM/MM/MD方法分析质子转移到双核Fe-CU复合物中的K-Pathway。 AIM 4。我们将进一步开发当前的方法，以提高这些大型活性站点模型的DFT计算质量，以QM/MM/MD分析动态过程，以及对剩余蛋白/膜/膜/水溶液环境的物理描述。线粒体的细胞色素C氧化酶（复合物IV）通过电子传输链将电子转移与大多数有氧细菌中的质膜连接到穿过线粒体内膜的质子。这是用于ATP生产的质子动力。线粒体CCO在人类健康中起着至关重要的作用，因为最重要的代谢功能需要足够的ATP供应。同样，电子或质子转移反应的破坏或在CCO处的氧结合可以导致产生破坏性的活性氧，包括羟基和超氧化物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和癌症很重要，并且也与衰老的病理学有关。