title: Metal-binding affinity and selectivity of nonstandard natural amino acid residues from DFT/CDM calculations.
abstract: Unnatural amino acid residues are increasingly being used in metalloprotein design and engineering to expand the repertoire of protein structures/folds and functions. However, natural but nonstandard amino acid residues (not in the basic set of 20) possessing metal-ligating groups such as selenocysteine (Sec), pyrrolysine (Pyl), and gamma-carboxyglutamic acid (Gla) have attracted little attention, and their potential as metal-binding entities in metalloprotein engineering has not been assessed. In particular, the metal-binding affinity/selectivity of these three rare residues remains unclear. Herein, the metal-binding affinity/selectivity of the Gla, Pyl, and Sec side chains have been systematically studied using a combined density functional theory and continuum dielectric method. The calculations reveal an advantage of using these noncanonical protein building blocks instead of the standard 20 amino acid residues. Gla2-, Pyl0, and Sec- have greater potential in trapping the metal cation than their standard amino acid counterparts. They prefer binding to Zn2+ rather than to Mg2+ or Ca2+ in a protein cavity due to the better electron-accepting ability and lower coordination number preference of Zn2+, as compared to Mg2+ and Ca2+. Between Ca2+ and Mg2+, Gla2- prefers Ca2+, whereas Pyl0 and Sec- poorly discriminate between the two metal cations. The results herein suggest that Gla2-, Pyl0, and Sec- could be employed as very efficient metal-binding entities in engineering metalloproteins with preprogrammed properties.
authors: Institute of Biomedical Sciences, Academia Sinica, Taipei 115, Taiwan, and the Department of Chemistry, National Tsing Hua University, Hsinchu 300, Taiwan.
authors: Todor
authors: T
authors: Dudev
authors: Carmay
authors: C
authors: Lim
mesh_terms: D015055:1-Carboxyglutamic Acid / Q000737:chemistry*; D001665:Binding Sites; D003198:Computer Simulation; D008239:Lysine / Q000031:analogs & derivatives* / Q000737:chemistry; D008670:Metals / Q000737:chemistry*; D008956:Models, Chemical; D017279:Selenocysteine / Q000737:chemistry*; D055672:Static Electricity
chemical_list: D008670:Metals; D017279:Selenocysteine; D015055:1-Carboxyglutamic Acid; C456839:pyrrolysine; D008239:Lysine