Quantum Chemistry of Proton Pumping by Cytochrome c Oxidases

描述（由申请人提供）：提议的工作涉及几何和电子结构的密度泛函理论（DFT）计算，静电计算和量子力学\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c氧化酶（CcO）进行比较。目的1。建立量子/静电模型，解释Fe-Cu双核配合物（DNC）中的化学键和质子/电子流如何导致质子跨膜泵送。QM/MM/MD研究将提供对DNC内部质子转移和质子退出通道的动态过程的见解。目标2。过氧桥接Fe-Cu的检测和表征将与DFT中相应的电子态有关。将进行振动谱和其他电子特性（穆斯堡尔和光学）的DFT计算，以便与实验谱进行比较。目标3。利用DFT/静电学和QM/MM/MD方法分析质子转移到双核Fe-Cu配合物中的k途径。目标4。我们将进一步发展现有的方法，以提高这些大型活性位点模型的DFT计算质量，用QM/MM/MD分析动态过程，以及对剩余蛋白质/膜/水溶液环境的物理描述。线粒体的细胞色素c氧化酶（复合体IV）通过电子传递链将电子传递到质子泵送，穿过线粒体的内膜，类似地，在大多数需氧细菌中，穿过质膜。这是用于ATP生产的质子动力。线粒体CcO在人体健康中起着至关重要的作用，因为足够的ATP供应是最重要的代谢功能所必需的。此外，电子或质子转移反应或CcO上氧结合的中断会导致产生有害的活性氧，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和癌症非常重要，也与衰老的病理有关。

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.