Pep2MARS: Automated Cyclic Peptide Parameterization for Molecular Dynamics and Compound Design

Cyclic peptide represents an attractive drug modality with its advantages in targeting proteins that were traditionally considered "undruggable". Molecular dynamics (MD) simulation remains a powerful tool for understanding peptide conformations and their interactions with the corresponding receptors in complex form. However, the preparation of macrocyclic peptide parameter files consisting of nonproteinogenic amino acids can be time-consuming and error prone. Here, we introduce an automatic workflow for the preparation of topology and force field parameter files for cyclic peptide systems. Partial charges and force field parameters of nonproteinogenic amino acids are automatically processed in a widely adopted rigorous way. Peptides spanning from mono- to tetra-cyclization were tested in bound and unbound states, which yielded valid parameter files and similar simulation results to those generated by different MD engines. Overall, the tool chain streamlines macrocyclic peptide MD setup while maintaining rigor and transferability across diverse cyclization patterns and simulation engines.