Joëlle Mérgola-Greef, Bruce F. Milne
This work presents a computational investigation of cyclic peptide membrane permeability through conformational ensemble analysis, evaluating free energy, conformational flexibility, solvent-accessible surface area (SASA), polar surface area (PSA), apolar surface area (APSA), molecular volume, and ensemble entropy as physicochemical descriptors. A central methodological contribution is the separate analysis of 6-membered and 7-membered cyclic peptides, which reveals ring-size-dependent structure-permeability relationships obscured by the unified treatment employed in prior studies. For 6-membered peptides, more negative free energy changes between water and octanol, larger SASA and APSA, lower Volume/SASA ratios, and Boltzmann-weighted PSA in octanol all show significant correlations with permeability. For 7-membered peptides, covalent flexibility emerges as the dominant predictor. Intramolecular hydrogen bond count correlates positively with permeability for 6-membered peptides in both solvents and for 7-membered peptides in octanol, while ensemble entropy shows no significant correlation in either subset. These findings demonstrate that cyclic peptide membrane permeability is governed by a ring-size-dependent interplay of thermodynamic stability, covalent flexibility, and hydrophobic surface characteristics, underscoring the necessity of ring-size-stratified analysis for meaningful structure-permeability relationships.