This chapter focuses on those systems for which information about metal ion coordination is available. In the past decade, however, some details of metal binding have begun to emerge from spectroscopic and crystallographic studies. The coordination chemistry of metal homeostatic proteins is not well understood due to a lack of biochemical and biophysical data. 4,5 Proteins in both families maintain concentrations of both essential and nonessential metal ions. 3 The metalloregulatory proteins utilize metal ions to regulate gene expression. The metal trafficking proteins include membrane transporters that translocate metal ions across cell membranes 2 and soluble metallochaperone proteins that deliver metal ions to specific target proteins. Proteins involved in metal ion homeostasis can be divided into two broad families, metal trafficking proteins and metalloregulatory proteins. Moreover, an increasing number of human diseases are linked to deficiencies in metal handling. Understanding these systems on the molecular level is a fundamental problem in biological coordination chemistry. Since the early 1980s, a number of metal homeostatic systems in both eukaryotes and prokaryotes have been discovered by genetic techniques. Therefore, intracellular transition metal ion concentrations must be controlled carefully to ensure that metal ions are provided to essential metalloproteins and metalloenzymes, but do not accumulate to toxic levels. Second, metal ions can bind nonspecifically to amino acid residues, replacing existing metal ions in enzyme active sites or key structural sites, leading to aberrant activity or protein misfolding. First, redox active metal ions such as copper and iron can generate highly reactive hydroxyl radicals and cause oxidative damage to proteins, nucleic acids, and lipids. The dual nature of metal ions derives from two properties. 1 However, metal ions can also be deleterious. Transition metal ions are essential cofactors for proteins with diverse functions, including electron transfer, dioxygen binding and activation, nitrogen fixation, and antioxidant defense. Rosenzweig, in Comprehensive Coordination Chemistry II, 2003 8.8.1 Introduction Results of these studies will help in designing metal-binding motifs in proteins with varying interaction strengths.R.L. Our studies suggest the factors that could explain why Met is not as frequently observed as Cys in the metal-binding motifs. Interaction of the wild-type motif with the copper ion is ~ 160 kcal/mol weaker than that of mutated motif. We also considered Met → Cys − mutation in the motif and repeated the calculations. We then considered the entire metal-binding motif with four residues and calculated the interaction energies with the copper ion. However, Cys − interactions with copper is stronger than that of Met by ~ 250 kcal/mol. On average, interactions of Met with copper ion are stronger by 13–35 kcal/mol compared to CysH. We also carried out calculations with wild-type Cys present in the same metal-binding motif. To compare the metal-binding strength, we mutated Met in silico to CysH/Cys − and performed the calculations. We used two different levels of theory (B3LYP and M06-2X) and the model compounds methyl propyl sulfide, ethanethiol and ethanethiolate were used to represent Met, CysH and Cys − respectively. In the case of Cys, both neutral (CysH) and the deprotonated form (Cys −) were considered. We performed quantum chemical calculations to find out the strength of interactions between sulfur and metal ion in both Met and Cys residues. To address methionine's lower preference in copper-binding sites in comparison to cysteine, we have considered copper-binding motifs (His-Cys-His-Met) from seven different high-resolution protein structures. Although cysteine sulfur is more frequently found as metal-binding ligand, methionine prefers to occur in copper-binding motifs of some proteins. Metals play vital role in various physiological processes and are bound to biomolecules.

Metal ion bonding methionine