The objective for this proposal is the development of theoretical models for chromophores in biologically important metalloproteins. The methods to be employed include analysis of optical experiments of various types (e.g., absorption, resonance Raman, circular dicroism, and photochemical holeburning) and a novel method for carrying out accurate ab initio electronic structure calculations for large chromophores in a realistically parametrized protein environment which is expected to be two orders of magnitude faster than conventional techniques. The combination of these approaches will allow determination of the important electronic (exchange matrix elements, excitation energies, oxidation and spin states, redox potential) and nuclear (ground and excited state equilibrium geometry, vibrational force fields) parameters which characterize the in vivo chromophore at a level superior to previous efforts. The key factors leading to enhanced results include substantially improved numerical algorithms, extensive collaboration with experimental groups, and development of efficient, mated computer codes. The metalloproteins to be studied include the blue copper proteins, iron-sulfur proteins, heme proteins, and the photosynthetic reaction center. A particular focus will be on electron transport processes; for photosynthetic primary charge separation, a detailed dynamical model will be developed and compared with experimental results. For the remaining proteins, systematic studies of both model compounds and a series of related proteins will be carried out in order to establish correlations of chromophore properties with spectroscopic observables. The importance of metalloproteins in the respiratory electron transport chain and in oxygen transport is self-evident. The ability to reliably interpret in vivo spectroscopic experiments on these systems and to construct significantly improved theoretical models of the chromophore and its interaction with the protein is fundamental to the goal of developing predictive capabilities for biological systems at the molecular level. The long term, health- related benefits of such a research program are the application of the improved theoretical models to the design of drugs targeted towards, e.g., metabolic disorders. Determination of the factors which control electron transport efficiency and ligand binding and the capacity to predict the effects of chemical modifications on these properties should greatly facilitate the drug design process.
