Tunable helicity, stability and DNA-binding properties of short peptides with hybrid metal coordination motifs

Abstract

Given the prevalent role of α-helical motifs on protein surfaces in mediating protein-protein and protein-DNA interactions, there have been significant efforts to develop strategies to induce α-helicity in short, unstructured peptides to interrogate such interactions. Toward this goal, we have recently introduced hybrid metal coordination motifs (HCMs). HCMs combine a natural metal-binding amino acid side chain with a synthetic chelating group that are appropriately positioned in a peptide sequence to stabilize an α-helical conformation upon metal coordination. Here, we present a series of short peptides modified with HCMs consisting of a His and a phenanthroline group at i and i+7 positions that can induce α-helicity in a metal-tunable fashion as well as direct the formation of discrete dimeric architectures for recognition of biological targets. We show that the induction of α-helicity can be further modulated by secondary sphere interactions between amino acids at the i+4 position and the HCM. A frequently cited drawback of the use of peptides as therapeutics is their propensity to be quickly digested by proteases; here, we observe an enhancement of up to ∼100-fold in the half-lifes of the metal-bound HCM-peptides in the presence of trypsin. Finally, we show that an HCM-bearing peptide sequence, which contains the DNA-recognition domain of a bZIP protein but is devoid of the obligate dimerization domain, can dimerize with the proper geometry and in an α-helical conformation to bind a cognate DNA sequence with high affinities (Kd≥ 65 nM), again in a metal-tunable manner.

Metal-Dependent DNA Recognition and Cell Internalization of Designed, Basic Peptides

“…We also proved that an analogous complex featuring nitrate instead of chloride ligands Pd­(bipy)­(NO 3 ) 2 is also a very efficient binding trigger (Figure S12). Therefore, it appears that square planar cis -Pd­(II) complexes present the ideal coordination properties to promote an effective folding, and interaction to the target DNA . Notably, similar PtCl 2 complexes were ineffective, most probably because of the low reactivity and kinetic stability of the precursor salts (Figure b).…”

Role of Mono- and Divalent Ions in Peptide Glu-Asp-Arg–DNA Interaction

“…Peptides associated with metals can play an important role in such complexes. 13 Short peptides do not show immunogenicity. The mechanism of the biological activity of short peptides has not been yet fully understood.…”

“…It is known that gene expression relies on the controlled combination of DNA-binding proteins. Peptides associated with metals can play an important role in such complexes …”

Theoretical Investigation of the Newly Designed Benzimidazole Based Metal Mediated DNA Base Couples with DFT Method

“…The most basic indicators that allow storing, transferring and copying of the genetic information within these nuclear acids are hydrogen bonded Watson-Crick base pairs. Having metal coordination bonds instead of hydrogen bonds presents alternative and completely different base pairs [5] [6] [7]. As known, the event of binding a metal ion to a molecule affects the characteristics of UV-visible spectrum of molecule.…”