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Ensemble modeling reveals sensitivity to modifications in macrocyclic peptides, indicating potential for altered binding characteristics.
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.
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Martínez‐Noa et al. (2026) studied this question.
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