DFT and DFT/MM Investigations of the Fe(III) Center in Nitrile Hydratase

University Of Florida, Gainesville FL

Investigators

Abstract

Nigel Richards of the University of Florida is supported by the Theoretical and Computational Chemistry Program and the Molecular Biophysics Program to perform a series of quantum mechanical studies on nitrile hydratase (NHase), a non-heme, Fe(III)-containing enzyme of commercial significance. The project has three specific aims: (1) to evaluate the utility of density functional theoretical (DFT) methods in predicting the spin-state preferences of Fe(III) complexes that are models for the NHase metal center, (2) to model the UV-visible spectroscopy of Fe(III) complexes that are models of the NHase metal center using a combination of the INDO/S semiempirical model and hybrid DFT/molecular mechanics (MM) force field methods, and (3) to investigate the utility of DFT/MM calculations in probing the electronic structure of the NHase Fe(III) active site and the enzyme mechanism. The theoretical description of NHase is expected to impact research in several areas. First, NHase has potential applications in the "green" synthesis of stereochemically complex compounds, particularly if substrate specificity can be re-engineered on the basis of structural and mechanistic information. Next, insight into the role of the metal center in catalysis, and its interactions with the protein, are expected to stimulate the rational discovery of novel inorganic catalysts for the hydration of commercially important nitriles. Finally, modeling the structure and reactivity of the non-heme Fe(III)-center in NHase will be a robust test of the utility of modern hybrid quantum mechanical molecular mechanics methods and density-functional theory techniques for modeling metalloenzymes. Recent advances in theoretical methods have opened the possibility of new computational studies into the structure, reactions, and catalysis of transition metal-containing enzymes, which often mediate critical steps in the biosynthesis of both primary and secondary metabolites. In this project, modern computational approaches will be used to calculate the properties of these enzymes, which are expected to have future importance in pharmaceutical discovery using metabolic engineering, and industrial chemical synthesis using biotechnological methods.