Ensemble Sensitivity to Chemical Modifications in Free and Bound Macrocyclic Peptides

Macrocyclic peptides present a challenging regime for molecular modeling in which minimal chemical modifications can strongly reweight conformational ensembles while leaving binding function largely intact. The combination of topological constraint, residual flexibility, and noncanonical linkages complicates both conformational sampling and force-field parametrization, particularly when differences in binding arise from ensemble redistribution rather than distinct bound geometries.