Theoretical Study of Charge Transfer in Cytochrome C Oxidase

描述(申请人提供)：这个项目的总体目标是通过计算机模拟促进对呼吸电子传递链的末端酶--细胞色素C氧化酶(CcO)中质子泵的原理和分子机制的理解。该酶的晶体结构早在十年前就已经解决；然而，其质子泵的分子机制仍不清楚。在拟议的工作中，将研究该酶中发生的电子和质子转移反应，并将应用和进一步发展前一次资助期间开发的电子和质子转移的计算和理论方法。这项工作的重要部分致力于实验数据的分析和与实验小组的合作，产生具有预测能力的严谨理论来指导实验。 具体目标包括： 1.研究了CcO中氧化还原中心之间的电子隧穿，以及Pr态的形成机理。 2.细胞色素C氧化酶产生膜电位的理论。 3.计算了CcO在催化循环中不同氧化还原态的质子化态。这个 寻找质子泵元件和质子出口地点。 4.细胞色素c中电子和质子耦合转移反应能垒的计算 化学质子和泵浦质子的动力学选通机制的研究。 与公众健康相关这项工作是我们长期目标的一部分，目的是绘制线粒体的整个电子传输链，研究质子泵、氧还原和活性氧物种(ROS)的产生机制。越来越多的证据表明，线粒体电子传输链的功能障碍和自由基的产生正在导致细胞衰老、细胞凋亡和许多人类心脏和大脑的退行性疾病，这突显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.