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计算机模拟加深对呼吸电子传递链末端酶细胞色素c氧化酶（CcO）质子泵送原理和分子机制的理解。这种酶的晶体结构在十年前就被解开了；然而，其质子泵送的分子机制尚不清楚。在这项工作中，将研究在这种酶中发生的电子和质子转移反应；在前一个资助期内发展的电子和质子转移的计算和理论方法将得到应用和进一步发展。相当一部分工作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，可以指导实验。

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.