DESCRIPTION (provided by applicant): Hemoproteins play essential roles in a wide range of biological systems, including oxygen transport and storage (hemoglobin and myoglobins), oxygen metabolism (oxidases, peroxidases, catalases, and hydroxylases), and electron transfer (cytochromes). This proposal is for a state-of-the-art theoretical study of the interaction of several biologically relevant small-molecule ligands with various hemoproteins. In addition to describing the ligand-heme interaction with advanced density-functional theory (DFT) methodology, the proposed work will model the interaction with the protein environment. The latter is thought to be vital for the various functions of hemoproteins, but its role is not well understood. It has received little attention in theoretical studies, in part because of the large computational demands of doing so. We propose to study the ligand, the heme group, and their interaction with the protein environment using hybrid quantum mechanics/molecular mechanics (QM/MM) methodology. The QM treatment will be performed using DFT, augmented with a recently developed correction for dispersion interactions, with which a reliable description of intermolecular interactions (e.g. between the protein environment and the ligand-heme complex) is possible. The QM treatment will be performed on the ligand, heme, and the closest protein residues. The Amsterdam Density Functional (ADF) and Gaussian03 software will be used. The effect of the protein environment on four properties will be investigated: (1) The structure, interaction energy, and kinetic parameter for the binding of XO molecules (X = O, C, N) to Mb; (2) The ligand selectivity of soluble guanylate cyclase (sGC)-like heme domains; (3) The structure and energetics of the active intermediates in the catalytic cycle of cytochrome P450s; (4) The electronic structure of heme oxygenase complexes with azide, OH, and OOH species. Hemoproteins are critical components of many living systems, including humans. They consist of two parts, the metal-containing heme part and the protein part. The proposed work is a computational modeling study of hemoproteins that will include the protein part in the model. The results will provide information on how their different protein parts enable different hemoproteins to perform their specific functions.