Parallel Temperature Replica-Exchange Molecular Dynamics Simulations Capture the Observed Impact of Stapling on Coiled-Coil Conformational Stability

• DOI: 10.1021/acs.jpcb.4c06974
• Publication Date: 2025-01-09T21:39:23Z
• Authors: Joshua L. Price
• Keywords: Force Field; Coiled coil; Solvent models

Macrocyclization or stapling is an important strategy for increasing the conformational stability and target-binding affinity of peptides proteins, especially in therapeutic contexts. Atomistic simulations such stapled proteins could help rationalize existing experimental data provide predictive tools design new proteins. Standard approaches exist incorporating nonstandard amino acids functional groups into force fields required MD have been used context more than a decade. However, enthusiasm their use has limited by time-intensive nature concerns about whether resulting would be physically realistic. Here, we report development field parameters two unnatural triazole staples, which incorporated implicit-solvent parallel temperature replica-exchange molecular dynamics several coiled-coil variants nonstapled counterparts. We these to calculate melting temperatures (Tm) each variant along with impact on relative its counterpart (ΔΔG). Trends among simulated Tm ΔΔG values closely match those observed previous experiments, suggesting that developed staples are sufficiently realistic useful predicting protein/peptide other