Diketopiperazine Formation from FPGK (n = 1-9) Peptides: Rates of Structural Rearrangements and Mechanisms.

Area of Science:

• Chemical Kinetics
• Mass Spectrometry
• Ion Mobility Spectrometry

Background:

• Peptides with penultimate proline residues can undergo isomerization and cleavage, forming diketopiperazines (DKPs).
• Understanding peptide dissociation mechanisms is crucial for various biochemical applications.

Purpose of the Study:

• To investigate the dissociation kinetics of Phe-Pro-Gly-Lys peptides (n=1-9) in ethanol.
• To elucidate the role of peptide length and conformation in DKP formation and bond cleavage.

Main Methods:

• Ion mobility spectrometry and mass spectrometry were employed to study dissociation kinetics.
• Molecular dynamics simulations were used to analyze peptide conformations and interactions.
• Temperature-dependent kinetics measurements provided thermochemical data.

Main Results:

• Shorter peptides (n=1-3) exhibited greater stability than longer peptides (n=4-9).
• Intramolecular hydrogen bonding and N-terminal charge influenced peptide stability and DKP formation.
• Transition state thermochemistry (ΔG‡, ΔH‡, ΔS‡) was determined for the bond cleavage process.

Conclusions:

• Peptide length significantly impacts stability, with shorter peptides being more resistant to DKP formation.
• Conformational stabilization through hydrogen bonding and N-terminal protonation plays a key role in inhibiting peptide bond cleavage.
• The study provides detailed insights into the mechanism and energetics of peptide dissociation via DKP formation.