Evolving Trends in Transition Metal-Modified Receptor Design and Function - Designing Receptors for the Next Generation of Biosensors - page 237

they contain relatively small structural domains stabilized by one or more Zn(II)
cations [ 5 ]. The Zn(II) sites induce the correct folding of surrounding peptide
fragments through tetrahedral coordination resulting in finger-like protrusions
from the local protein structure that make tandem contacts with target molecules.
Such zinc finger motifs commonly function as recognition modules that bind DNA,
RNA, proteins, or small molecules. Hence, these proteins are involved in many
fundamental cellular processes such as transcription and translation, replication and
repair, cell proliferation and apoptosis, metabolism, and cell signaling [ 6 ].

2.1 Metal-Directed Peptide Assemblies for Molecular Recognition

Inspired by native metalloproteins, there is significant interest in utilizing metal-
binding sites to prepare designed peptides and proteins as first steps toward novel
biosensor receptors and de novo enzymes [ 7 ]. Early work by Ghadiri and coworkers
[ 8 , 9 ] demonstrated that

-helical secondary structures could be stabilized by
selective metal complexation through judicious placement of either His or Cys
residues one turn apart in relatively short amphiphilic peptide chains. In these
examples, transition metal ions serve as intrapeptide crosslinks between i and
i + 4 amino acid positions that stabilize helix formation by diminishing the entropy
of the unfolded state relative to the folded state.
Furthermore, many groups have appended nonnatural synthetic ligands to pep-
tide chains to allow for metal-directed assembly of stable tertiary structures (for a
recent review, see [ 10 ]). For example, 2,2 0 -bpy ligands have gained prominence for
many reasons: (1) they readily form tris-chelated octahedral complexes with a
variety of transition metal precursors, (2) they serve as well-behaved spectroscopic
probes, and (3) the resulting metal complexes often have high thermodynamic and
kinetic stabilities. By covalently linking bpy ligands to the N -terminus of amphi-
philic peptide sequences, triple helical coiled coil tertiary structures have been
prepared upon coordination to Fe(II), Co(II), Ni(II), and Ru(II) precursors [ 11 - 14 ].
A schematic representation of such metal-directed trimeric coiled coils is shown
in Fig. 2 . The bpy-functionalized peptides are designed as short amphiphilic
sequences that are relatively unstructured in solution. In the presence of a six-
coordinate transition metal ion (M), a [M(bpy-peptide) 3 ] 2+ complex is formed. As
the metal complex forces the peptides into close proximity,

a

-helices are adopted,
as characterized by circular dichroism. Stable assembly in the presence of metal
ions is driven by burial of hydrophobic amino acid residues within the tertiary
structure.
In the context of synthetic receptors, the [M(bpy-peptide) 3 ] 2+ architecture is a
well-defined, robust, and easily synthesized construct for molecular recognition
studies. The 2,2 0 -bpy ligands can be linked to any helical peptide sequence via
solid-phase peptide synthesis. Gochin et al. have employed [M(bpy-peptide) 3 ] 2+
complexes using Fe(II) and Ni(II) ions to screen protein-peptide and protein-ligand
interactions of the trimeric coiled coil subunit gp41 from the envelope glycoprotein

a