The specific aims of our proposed research program continue to focus on the problems and mechanisms of molecular recognition. Through the broad long term objectives of this research application we seek to understand the molecular mechanisms of metalloenzyme function, with specific focus on the mechanisms by which biological macromolecules recognize other macromolecular and small organic structures. Primary goals are to understand the detailed process for: (1) the recognition of a small substrate/inhibitors by a protein, (2) the structure and dynamics of specific protein - protein complexes involved in metalloprotein catalysis and (3) the mechanisms for specificity in recognition of nucleic acids by proteins. A corollary aim of our research is to develop and apply new and novel physical and chemical techniques to solve the questions of molecular recognition.
Our aim i s for these technological advances to have broad applicability to a wide variety of systems and be incorporated into the repertoire of other scientists. The question of molecular recognition is a central paradigm of molecular biology, playing central roles in most, if not all, cellular processes. Failed recognition events have been implicated in numerous disease states ranging from flawed control of gene regulation and cellular proliferation, to defects in specific metabolic activities. Our use of recombinant DNA technology, in concert with advanced biophysical methods, has proven to be ideal for understanding the fundamental mechanisms of recognition in metalloenzyme systems. Our proposed research thrust in biological oxidations utilizes as exemplary systems the cytochromes P450 which play central significance in the biotransformations of human hepatic and adrenal tissue and in the plethora of oxidative metabolism that exist across the eukaryotic, procaryotic and archaea divisions of life. Thus, the central problems of metalloenzyme biology, chemistry, and biophysics will be attacked through the selective choice of the tractable systems proposed in this application, and the combined use of recombinant DNA technology and state of the art structure-function characterization in order to place molecular mechanisms on a firm foundation for scientific understanding.
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