Theoretical Studies of Metalloprotein Chromophores

Columbia Univ New York Morningside, New York NY

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Abstract

This project has two major objectives (1) development of new technology for computational modeling of metalloprotein active sites; (2) application of the methods to biologically important problems. Methodology development is focused ab initio quantum chemistry, mixed quantum mechanical/classical mechanical simulation techniques, continuum solvation models, evaluation of free energy differences, and new algorithms for sampling large scale conformational changes. Metalloproteins to be studied in this granting period include methane monooxygenase, hemerythrin, cytochrome P450, myoglobin, hemoglobin, ribonucelotide reductase, and various iron-sulfur I Proteins. We also propose to initiate an effort to apply our method to the study of small metal Icontaining molecules, such as cisplatin (a major anticancer drug), binding to DNA. Results to be Iobtained from the calculations include characterization of reactant and product structures, reactive lintermediates, and transition states at an atomic level of detail, as well as computation of enthalpies land free energies for these various species.