Theoretical Studies of Biological Charge Transfer

细胞色素氧化酶（考克斯）是线粒体内呼吸系统电子传递链的末端组分，是细胞能量产生的关键酶之一。考克斯是一个质子泵。提出的研究的总体目标是在这种酶和质子泵的能量转换的原则和分子机制的理解。在拟议的工作中发生的电子和氧化还原耦合质子转移反应的考克斯将进行调查，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将应用和进一步推进。具体项目包括：1）计算酶四个氧化还原位点链上的电子转移速率和沿着路径;应用、测试和进一步改进上一个资助期开发的Tunnel Current方法。分析蛋白质中ET的音位学模型（当和乳清时，它们适用于蛋白质）。考克斯动力学模拟及动力学效应对电子转移的影响。2)计算酶的质子化状态作为其氧化还原状态的函数，用于沿着催化循环的各个步骤;开发用于此类计算的同质蛋白质计算模型。关键质子化氨基酸突变效应的鉴定和研究。3)D-和K-通道中氧化还原偶联质子转移的研究。模拟酶中的水。电子耦合质子转移反应自由能速率之研究。研究控制电子和质子转移反应速率的因素，以及酶的整个循环。4)发展质子泵的唯象动力学模型，研究其效率、动力学要求和一般热力学原理。这些研究将有助于对生物能量转换的分子理解，并将为氧化还原蛋白质的研究提供新的计算工具。

Cytochrome oxidase (COX) is the terminal component of electron transport chain of the respiratory system in mitochondria, and one of the key enzymes responsible for energy generation in cells. COX is a proton pump. The general goal of the proposed studies is to advanced understanding of the principles and molecular mechanisms of energy transformations in this enzyme and proton pumping. In the proposed work the electron and redox coupled proton transfer reactions occurring in COX 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. The following specific projects will be undertaken: 1)Calculation of electron transfer rates and pathways along the chain of four redox sites of the enzyme; Application, test and further advancement of the Tunneling Current Method developed in the previous grant period. Analysis of phonemenological models of ET in proteins (when and whey they are applicable to proteins). Simulation of dynamics of COX and evaluation of the dynamic effects on electron transfer. 2) Calculation of the protonation state of the enzyme as a function of its redox state for various steps along the catalytic cycle; development of in homogenous protein computational models for such calculations. Identification and studies of the effects of mutations of key protonable amino acids. 3) Studies of the redox coupled proton transfer in D- and K-channels. Simulation of water in the enzyme. Studies of the free energy rates of electron coupled proton transfer reactions. Investigation of the factors that control rates of electron and proton transfer reactions, and the overall cycle of the enzyme. 4) Development of phenomenological kinetic models of proton pumps, investigation of their efficiency, kinetic requirements, and general thermodynamic principles. These studies will contribute to molecular understanding of biological energy transformations, and will result in new computational tools for investigation of redox proteins.