Theoretical Studies of Biological Charge Transfer

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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.