Metallopeptide design: Tuning the metal cation affinities with unnatural amino acids and peptide secondary structure

The ability to tune the metal binding affinity of small peptides through the incorporation of unnatural multidentate alpha-amino acids and the preorganization of peptide structure is illustrated. Herein, we describe the exploitation of a family of alpha-amino acids that incorporate powerful bidentate ligands (bipyridyl and phenanthrolyl groups) as integral constituents of the residues' side chains. The residues involved are the 6-, 5-, and 4-substituted (S)-2-amino-3-(2,2'-bipyridyl)propanoic acids (1, 6Bpa; 2, 5Bpa; 3, 4Bpa), (S)-2-amino-3-(1,10-phenanthrol-2-yl)propanoic acid (4, Fen), and a novel neocuproine-containing alpha-amino acid, (S)-2-amino-3-(9-methyl-1,10-phenanthrol-2-yl)propanoic acid (5, Neo). Within this family of amino acids, variations in metal binding due to the nature of the ring system (2,2'-bipyridyl or 1,10-phenanthrolyl) and the point of attachment to the amino acid beta-carbon are observed. Additionally, the underlying peptide architecture significantly influences binding for peptides that include multiple metal-ligating residues. These differences in affinity arise from the interplay of ligand type and structural preorganization afforded by the peptide sequence, resulting in dissociation constants ranging from 10(-3) to <10(-6) M for Zn-II. These studies illustrate that significant control of metal cation binding affinity, preference, and stoichiometry may be achieved through the use of a wide variety of native and unnatural metal-coordinating amino acids incorporated into a polypeptide architecture.