NEAR ULTRAVIOLET RAMAN STUDIES OF CYTOCHROME P450

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DESCRIPTION: (adapted from applicant's abstract) The aim of this proposal is to extend the understanding of the structure and function of cytochrome P450 and other heme protein systems by using Raman spectroscopy and femtosecond coherence spectroscopy (FCS), which directly probes the coherent protein/cofactor vibrational motion induced by electronic transitions associated with biochemical reactions. Overall, this project has a wide range of health related implications involving P450 in particular and hemes in general. Many chemotherapeutic agents as well as polycyclic carcinogens are metabolized by P450 systems. Moreover, all metabolic disorders involving a P450 protein relate to this work since a fundamental understanding of the active site structure and function of P450 at the molecular level will result in better insight for those concerned with treatment of these disorders at any level. These studies will employ spectroscopic measurements that allow key, reaction specific electronic and electron-nuclear coupling parameters to be extracted from the combination of x-ray structure and FCS data. Careful studies of the reaction and field driven coherences as a function of temperature, viscosity, and protein perturbations will be carried out in order to better assign and understand the nature of the coherent states that are formed as the reactions proceed. Time resolved protein dynamics and kinetics will be followed over many orders of magnitude, from femtoseconds to kiloseconds, and novel double-pulse kinetics experiments will be used to probe rapidly reacting subpopulations of the ensemble so that protein conformational interconversion times are directly revealed. Theoretical work involving ligand binding and dissociation in heme proteins, reaction coherence, electron transfer, and resonant light-matter interactions will also be pursued.