Quantum Chemistry of Proton Pumping by Cytochrome c Oxidases

拟议的工作涉及几何和电子结构的密度泛函理论（DFT）计算， 静电学计算和量子力学/分子力学/分子动力学（QM/MM/MD） 模拟，以提供催化反应途径的详细机理理解， B型和A型细胞色素c氧化酶（CcO）中的质子泵机制。 目标1.开发一个量子/静电模型，解释化学键合和质子/电子如何流动， Fea3-CuB双核络合物（DNC）内的分子氧导致质子泵送穿过 膜的QM/MM/MD研究将提供对质子摄取、质子转移和质子转移的动态过程的深入了解。 在DNC和质子从DNC出口通道内。 目标2. Fe-Cu物质之间和/或桥接Fe-Cu物质的各种氧物质的检测和表征 将与来自DFT的相应电子状态相关。振动光谱和其他的计算 电子性质（穆斯堡尔）将执行连接我们的假设与实验 光谱学 目标3.将获得B-的高分辨率、低辐射损伤的新的单晶X射线结构。 CcO型来自嗜热栖热菌。这些将被分析，与其他结构和DFT相比， 计算。 目标4。我们将进一步发展现有的方法，以提高量子化学DFT的质量 计算这些大的活性部位模型，分析与QM/MM/MD动态过程， 以及用于剩余蛋白质/膜/水性溶剂环境的物理描述。 线粒体的CcO（复合物IV）通过电子传递链将电子传递连接到质子 泵送穿过线粒体的内膜，类似地，在大多数情况下穿过质膜。 需氧细菌这是用于ATP生产的质子动力。线粒体CcO的作用 在人类健康中起着重要作用，因为最重要的代谢需要足够的ATP供应。 功能协调发展的此外，电子或质子转移反应或CcO处的氧结合的中断可导致CcO的断裂。 产生破坏性活性氧物质，包括羟基和超氧自由基，以及氢 过氧化物了解线粒体CcO的结构、机制和功能对于 更好地分析了许多遗传和代谢疾病和癌症，也与病理学有关， 衰老

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 and mechanisms of proton pumping in B-type and A-type cytochrome c oxidases (CcO's). Aim 1. Develop a quantum/electrostatic model explaining how chemical bonding and proton/electron flow to molecular oxygen within the Fea3-CuB dinuclear complex (DNC) leads to proton pumping across the membrane. QM/MM/MD studies will provide insights into dynamic processes of proton uptake, proton transfer within the DNC and the proton exit channel from the DNC. Aim 2. Detection and characterization of various oxygen species between and/or bridging the Fe-Cu species will be related to corresponding electronic states from DFT. Calculations of vibrational spectra and other electronic properties (Mössbauer) will be performed to connect our hypotheses with experimental spectroscopies. Aim 3. New single crystal X-ray structures at high resolution with little radiation damage will be obtained for B- type CcO from Thermus thermophilus. These will be analyzed in comparison to other structures and DFT calculations. Aim 4. We will further develop current methodologies to improve the quality of quantum chemical 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. CcO (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.