Quantum Chemistry of Proton Pumping by Cytochrome c Oxidases

描述(申请人提供)：建议的工作包括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理理解，也与A型细胞色素c氧化酶(CcO)进行比较。目的1.建立一个量子/静电模型来解释铁铜双核配合物(DNC)中的化学键和质子/电子如何流向分子氧，从而导致质子泵过膜。QM/MM/MD研究将提供对DNC内质子转移和质子从DNC流出通道的动态过程的深入了解。目的2.过氧桥联Fe-Cu物种的检测和表征将与密度泛函理论中相应的电子态有关。将进行振动光谱和其他电子性质(穆斯堡尔和光学)的密度泛函计算，以便与实验光谱进行比较。目的3.用DFT/静电学和QM/MM/MD方法分析双核Fe-Cu络合物中质子转移的K途径。目的4.我们将进一步发展现有的方法，以提高这些大活性中心模型的密度泛函计算的质量，用QM/MM/MD分析动态过程，并对剩余的蛋白质/膜/水溶剂环境进行物理描述。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与质子泵过线粒体内膜相连，在大多数需氧细菌中也是如此。这是用于生产三磷酸腺苷的质子动力。线粒体CcO在人类健康中起着至关重要的作用，因为大多数重要的代谢功能都需要充足的ATP供应。此外，电子或质子转移反应的中断或CCOO上的氧结合可能会导致产生破坏性的活性氧物种，包括羟基和超氧阴离子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性疾病和癌症非常重要，也与衰老的病理学有关。

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.