Parallel Temperature Replica-Exchange Molecular Dynamics Simulations Capture the Observed Impact of Stapling on...

Area of Science:

• Biophysics
• Computational Chemistry
• Structural Biology

Background:

• Peptide and protein macrocyclization, or stapling, enhances conformational stability and target binding, particularly for therapeutic applications.
• Atomistic simulations offer predictive power for designing stapled peptides but face challenges with force field development and simulation realism.
• Existing methods for incorporating nonstandard amino acids into molecular dynamics (MD) force fields are time-consuming and raise concerns about physical accuracy.

Purpose of the Study:

• To develop and validate new force field parameters for unnatural triazole staples used in peptide macrocyclization.
• To assess the accuracy of these parameters in predicting the conformational stability of stapled peptides using molecular dynamics simulations.
• To provide a more reliable computational tool for the rational design of stapled peptides and proteins.

Main Methods:

• Development of novel force field parameters for two specific unnatural triazole staples.
• Incorporation of these parameters into implicit-solvent parallel temperature replica-exchange molecular dynamics (PTREXMD) simulations.
• Simulation of multiple stapled coiled-coil peptide variants and their nonstapled counterparts.

Main Results:

• Calculated melting temperatures (Tm) and the change in Gibbs free energy of unfolding (ΔΔG) for stapled and nonstapled peptide variants.
• Observed strong correlations between simulated Tm and ΔΔG values and experimentally determined trends.
• Demonstrated the physical realism of the developed force field parameters for triazole staples.

Conclusions:

• The newly developed force field parameters for triazole staples are sufficiently accurate for predicting the impact of stapling on peptide conformational stability.
• These parameters enable reliable molecular dynamics simulations, aiding in the rational design of novel stapled peptides for therapeutic purposes.
• The study validates the use of advanced simulation techniques for understanding and engineering peptide structure-stability relationships.