Theoretical Study of Charge Transfer in Cytochrome C Oxidase

描述（由申请人提供）：本项目的总体目标是通过使用计算机模拟来促进对细胞色素c氧化酶（CcO）（呼吸电子传递链的末端酶）中质子泵送的原理和分子机制的理解。这种酶的晶体结构在十年前就已经被解决了;然而，其质子泵的分子机制仍然未知。在拟议的工作中，发生在这种酶的电子和质子转移反应将进行调查;电子和质子转移的计算和理论方法，在以前的赠款期间开发的将被应用和进一步推进。工作的重要部分是致力于实验数据的分析和与实验组的合作，产生严格的理论与预测能力，可以指导实验。 具体目标包括： 1. CcO中氧化还原中心间电子隧穿的研究Pr态的形成机制。 2.细胞色素c氧化酶产生膜电位的理论。 3.计算CcO在催化循环中沿着不同氧化还原态的质子化状态。的 寻找质子泵元件和质子出口位置。 4.细胞色素c中电子和质子耦合转移反应能垒的计算 化学质子和泵送质子的动力学门控机制研究。 这项工作是我们长期目标的一部分，即绘制线粒体中的整个电子传递链，研究质子泵送，氧还原和活性氧（ROS）产生的机制。越来越多的证据表明，线粒体中电子传递链的功能障碍和自由基的产生导致细胞衰老、细胞凋亡以及人类心脏和大脑的许多退行性疾病，这强调了此类研究的重要性。

DESCRIPTION (provided by applicant): The general goal of this project is to advance understanding of the principles and molecular mechanism of proton pumping in Cytochrome c oxidase (CcO) - the terminal enzyme of the respiratory electron transport chain - by using computer simulations. The crystal structure of the enzyme has been solved a decade ago; however, the molecular mechanism of its proton pumping remains unknown. In the proposed work, electron and proton transfer reactions occurring in this enzyme will be investigated; the computational and theoretical methods for electron and proton transfer developed in the previous grant period will be applied and further advanced. Significant part of the work is devoted to analysis of experimental data and collaboration with experimental groups, producing rigorous theories with predictive power that can guide experiment. Specific aims include: 1. Study of electron tunneling between redox centers in CcO; The mechanism of Pr state formation. 2. Theory of membrane potential generated by cytochrome c oxidase. 3. Calculation of the protonation states of CcO for various redox states along its catalytic cycle. The search for proton pump element and the proton exit sites. 4. Calculation of energy barriers for coupled electron and proton transfer reactions in cytochrome c oxidase; Study of kinetic gating mechanism for chemical and pumped protons. PUBLICE HEALTH RELEVANCE This work is part of our long-term goal to map the whole electron transport chain in mitochondria, to study mechanisms of proton pumping, oxygen reduction, and generation of Reactive Oxygen Species (ROS). The importance of such studies is underscored by the growing evidence that the dysfunction of the electron transport chain in mitochondria and free radical production are contributing to cell aging, apoptosis, and to a number of degenerative diseases of the heart and brain in humans.