Modeling Modern Concepts in Metalloenzyme Active Site Reactivity

University Of Pennsylvania, Philadelphia PA

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Abstract

Project Summary The overarching goal of this chemistry is to develop new avenues in biomimetic transition metal chemistry as a way of modelling metalloenzyme active sites. This work is divided into two sections. The first aims to evaluate the ability of strong, local electrostatic fields in the secondary coordination sphere of a metal center to impact the metal’s electronic structure and reactivity profile. Electrostatic fields play critical roles in enzymology, and recent computational studies have provided the first indication that they operate at metalloenzymes. Lipoxygenases, blue copper proteins, photosystem II, and both heme and non-heme Fe centers have been variously predicted to use local electrostatic fields to facilitate electron transfer, proton transfer, or proton-coupled electron transfer (PCET). Preliminary results from our laboratory have mimicked the ability of enzymes to organize electric fields in a way that is advantageous to the active site’s chemistry. This electrostatic preorganization in our molecular compounds was then shown to regulate both O2 binding to CuI ions and the rates of subsequent intermolecular PCET chemistry. The proposed research will first delineate the extent to which electrostatic fields are able to gate PCET – a process of fundamental importance to metabolism. Unexpected trends in the preliminary data hint at interesting electrostatic field effects that will need to be investigated in a systematic fashion. Next, the use of secondary coordination sphere electrostatic effects will be explored for their ability to stabilize key intermediates that have been proposed to develop during O2 processing at various monocopper sites in biology. Electrostatic effects are expected to provide a useful shift in the energy landscape for stabilizing these species. Lastly, a new approach will be developed for identifying secondary coordination sphere electrostatic effects with X-ray absorption spectroscopy and density functional theory, based on the expectation that oriented electrostatic fields will tune the energies and intensities of XAS acceptor states. The broad scope of this section of the research program is intended to improve our ability to identify, tune, and use electrostatic fields in molecular transition metal systems, as is needed for creating effective biomimetics. In the second section of this research program, we will investigate the ability of constrained geometry cluster compounds to effect biologically relevant N2 fixation chemistry. Many metalloenzymes use multinuclear active sites for small molecule activation, but efforts to mimic their structures and catalytic activities have lagged, with most relying on mononuclear transition metal complexes. Recent developments in the study of the nitrogenase enzymes have identified constrained geometry dinuclear sites as the likely locations for N2 fixation. In preliminary investigations, we have made use of a ligand system that is able to constrain the positions of two metal centers housed within a macrocyclic framework. The diiron version of this complex has been shown to form a number of species that are relevant to mechanisms that have been put forward for N2 fixation at the nitrogenase enzymes. The proposed work will perform a step-by-step investigation into the ability of constrained geometry diiron sites to shuttle nitrogenous substrates along an N2 reduction pathway. Together, these two sections are expected to advance our understanding of ways in which metalloenzymes perform some of the most challenging transformations in biology.