Approximately one-half of all known protein crystal structures in the protein data bank (PDB) contain metal ion cofactors, which play vital roles in charge neutralization, structure, and function.1,2 These proteins range in size from 5000-107 Da with the metal ion corresponding to only on the order of 0.1 wt % of the molecule. Yet, for a wide range of these metalloproteins, the metal ion and its environment are key to the chemistry as these comprise the active site in catalysis. It is the purpose of this review to present the information content of spectroscopic methods, which allow one to focus in on the metalloactive site (Figure 1), define its electronic structure, evaluate the role of the protein in determining geometric and electronic structure, and elucidate the contributions of electronic structure to function. Metalloproteins are simply metal complexes but with remarkably intricate and complex ligands. The metal ion, clusters of metal ions bridged by oxide or sulfide ligands or equatorially chelated by N-heterocyclic ligands (heme, corrin, etc.), are bound to the protein through one or more of the endogenous ligand lone pair donors in Table 1. Note that for most of the donor groups, this requires deprotonation, and the metal ion competition with the proton for the free base lowers the effective pKA by at least several log units from those intrinsic values listed in Table 1. It is important to emphasize that for a number of the ligands in Tables 1 and 2, in particular phenolate, thiolate, oxo and sulfido, and the N-heterocyclic chelates, the metal complex exhibits extremely intense low energy charge transfer (CT) absorption bands, which reflect highly covalent ligand-metal bonds. These make major contributions to the electronic structure of an active site and can be affected by the geometry of the metal site and the orientation of the ligand-metal bond, which in turn can be influenced by the protein matrix. * To whom correspondence should be addressed. † Department of Chemistry, Stanford University. ‡ Stanford Synchrotron Radiation Laboratory, SLAC, Stanford University. 419 Chem. Rev. 2004, 104, 419−458
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