title: Comparison of metal-binding strength between methionine and cysteine residues: Implications for the design of metal-binding motifs in proteins.
abstract: Metals play vital role in various physiological processes and are bound to biomolecules. Although cysteine sulfur is more frequently found as metal-binding ligand, methionine prefers to occur in copper-binding motifs of some proteins. 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. We performed quantum chemical calculations to find out the strength of interactions between sulfur and metal ion in both Met and Cys residues. In the case of Cys, both neutral (CysH) and the deprotonated form (Cys-) were considered. 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. To compare the metal-binding strength, we mutated Met in silico to CysH/Cys-and performed the calculations. We also carried out calculations with wild-type Cys present in the same metal-binding motif. On average, interactions of Met with copper ion are stronger by 13-35kcal/mol compared to CysH. However, Cys-interactions with copper is stronger than that of Met by ~250kcal/mol. We then considered the entire metal-binding motif with four residues and calculated the interaction energies with the copper ion. We also considered Met→Cys-mutation in the motif and repeated the calculations. Interaction of the wild-type motif with the copper ion is ~160kcal/mol weaker than that of mutated motif. Our studies suggest the factors that could explain why Met is not as frequently observed as Cys in the metal-binding motifs. Results of these studies will help in designing metal-binding motifs in proteins with varying interaction strengths.
authors.affiliation: Department of Biological Sciences and Bioengineering, Indian Institute of Technology Kanpur, Kanpur 208016, India.
authors.forename: R N V
authors.initials: RNV
authors.lastname: Krishna Deepak
authors.affiliation: Department of Biological Sciences and Bioengineering, Indian Institute of Technology Kanpur, Kanpur 208016, India.
authors.forename: Brijesh
authors.initials: B
authors.lastname: Chandrakar
authors.affiliation: Department of Biological Sciences and Bioengineering, Indian Institute of Technology Kanpur, Kanpur 208016, India. Electronic address: rsankar@iitk.ac.in.
authors.forename: Ramasubbu
authors.initials: R
authors.lastname: Sankararamakrishnan
mesh_terms: D001665:Binding Sites; D003300:Copper / Q000737:chemistry; D003545:Cysteine / Q000737:chemistry; D015195:Drug Design; D008667:Metalloproteins / Q000737:chemistry*; D008670:Metals / Q000737:chemistry; D008715:Methionine / Q000737:chemistry; D008958:Models, Molecular; D054730:Protein Interaction Domains and Motifs; D011789:Quantum Theory
chemical_list: D008667:Metalloproteins; D008670:Metals; D003300:Copper; D008715:Methionine; D003545:Cysteine
keywords: Design of metal-binding motifs; Metal interactions in proteins; Metal ligand; Methionine-metal interactions; Quantum chemical calculations; Sulfur as metal ligand