Redox-Triggered Reversible Switching between Dynamic and Quasi-static α-Helical Peptides

Area of Science:

• Supramolecular Chemistry
• Chemical Biology
• Peptide Science

Background:

• Alpha-helical peptides are crucial biomolecules with diverse functions.
• Controlling peptide secondary structure, like helicity, is vital for designing functional peptides.
• Dynamic and static peptide structures have distinct properties and applications.

Purpose of the Study:

• To achieve reversible transformation between singly stapled dynamic and doubly stapled quasi-static alpha-helical peptides.
• To investigate the impact of redox-triggered disulfide bond conversions on peptide helicity and interconversion rates.
• To explore the influence of staple rigidity on the kinetics of right-handed (P) and left-handed (M) alpha-helix interconversion.

Main Methods:

• Synthesis of doubly stapled alpha-helical peptides incorporating both disulfide-based reversible and biphenyl-based fixed staples.
• Redox reactions utilizing tri-n-butylphosphine for reduction and 4,4'-dithiodipyridine for oxidation to interconvert peptide states.
• Kinetic studies in 1,1,2,2-tetrachloroethane to determine the half-life of helix transformation and assess P/M interconversion rates.

Main Results:

• Successfully demonstrated reversible transformation between dynamic (singly stapled, dithiol) and quasi-static (doubly stapled, disulfide) alpha-helical peptide forms.
• Achieved a ~10^3 fold alteration in the rate of P/M helix interconversion upon transformation from dynamic to static states.
• Identified a kinetically trapped (M)-rich form in the doubly stapled peptide, which converts to the thermodynamically stable (P)-rich form over approximately 44 days at 25°C.

Conclusions:

• Redox-triggered dithiol/disulfide conversions provide an effective strategy for controlling alpha-helix dynamics and stability.
• The developed system allows for significant modulation of P/M helix interconversion rates, offering a new tool for peptide engineering.
• Staple rigidity plays a key role in the kinetics of helix interconversion, with flexible staples facilitating faster transitions.