title: 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 atiandi+7positions 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 thei+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.
authors: Department of Chemistry and Biochemistry, University of California, San Diego, 9500 Gilman Dr., La Mia, USA.
authors: Sarah J
authors: SJ
authors: Smith
authors: Department of Chemistry and Biochemistry, University of California, San Diego, 9500 Gilman Dr., La Mia, USA.
authors: Robert J
authors: RJ
authors: Radford
authors: Department of Chemistry and Biochemistry, University of California, San Diego, 9500 Gilman Dr., La Mia, USA.
authors: Rohit H
authors: RH
authors: Subramanian
authors: Department of Chemistry and Biochemistry, University of California, San Diego, 9500 Gilman Dr., La Mia, USA.
authors: Brandon R
authors: BR
authors: Barnett
authors: Department of Chemistry and Biochemistry, University of California, San Diego, 9500 Gilman Dr., La Mia, USA.
authors: Joshua S
authors: JS
authors: Figueroa
authors: Department of Chemistry and Biochemistry, University of California, San Diego, 9500 Gilman Dr., La Mia, USA.
authors: F Akif
authors: FA
authors: Tezcan