Approaches to Introduce Helical Structure in Cysteine-Containing Peptides with a Bimane Group

An i-i+4 or i-i+3 bimane-containing linker was introduced into a peptide known to target Estrogen Receptor alpha (ER alpha), in order to stabilise an alpha-helical geometry. These macrocycles were studied by CD and NMR to reveal the i-i+4 constrained peptide adopts a 3(10)-helical structure in solution, and an alpha-helical conformation on interaction with the ER alpha coactivator recruitment surface in silico. An acyclic bimane-modified peptide is also helical, when it includes a tryptophan or tyrosine residue; but is significantly less helical with a phenylalanine or alanine residue, which indicates such a bimane modification influences peptide structure in a sequence dependent manner. The fluorescence intensity of the bimane appears influenced by peptide conformation, where helical peptides displayed a fluorescence increase when TFE was added to phosphate buffer, compared to a decrease for less helical peptides. This study presents the bimane as a useful modification to influence peptide structure as an acyclic peptide modification, or as a side-chain constraint to give a macrocycle.

Automated summary

The introduction of a bimane-containing linker into a peptide targeting Estrogen Receptor alpha was shown to stabilize alpha-helical geometry, with the constrained peptide adopting a 3(10)-helical structure in solution. The study also revealed that the bimane modification influences peptide structure in a sequence dependent manner, with fluorescence intensity of the bimane being influenced by peptide conformation.