THE EXTENDED ENVIRONMENT OF MONONUCLEAR METAL CENTERS IN PROTEIN STRUCTURES

The objectives of this and the following paper are to identify commona lities and disparities of the extended environment of mononuclear meta l sites centering on Cu, Fe, Mn, and Zn. The extended environment of a metal site within a protein embodies at least three layers: the metal core, the ligand group, and the second shell, which is defined here t o consist of all residues distant less than 3.5 Angstrom from some lig and of the metal core. The ligands and second-shell residues can be ch aracterized in terms of polarity, hydrophobicity, secondary structures , solvent accessibility, hydrogen-bonding interactions, and membership in statistically significant residue clusters of different kinds. Fin dings include the following: (i) Both histidine ligands of type I copp er ions exclusively attach the N-delta 1 nitrogen of the histidine imi dazole ring to the metal, whereas histidine ligands for all mononuclea r iron ions and nearly all type II copper ions are ligated via the N-e psilon 2 nitrogen. By contrast, multinuclear copper centers are coordi nated predominantly by histidine N-epsilon 2, whereas diiron histidine contacts are predominantly N-delta 1. Explanations in terms of steric differences between N-delta 1 and N-epsilon 2 are considered. (ii) Ex cept for blue copper (type I), the second-shell composition favors pol ar residues. (iii) For blue copper, the second Shell generally contain s multiple methionine residues, which are elements of a statistically significant histidine-cysteine-methionine cluster. Almost half of the second shell of blue copper consists of solvent-accessible residues, p utatively facilitating electron transfer. (iv) Mononuclear copper atom s are never found with acidic carboxylate ligands, whereas single Mn2 ion ligands are predominantly acidic and the second shell tends to be mostly buried. (v) The extended environment of mononuclear Fe sites o ften is associated with histidine-tyrosine or histidine-acidic cluster s.