Analysis of Structural Parameters Governing Membrane Permeability in Cyclic Peptides: A GFN2-xTB Structure-Property Relationship Study

ChemRxiv

Abstract

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.

Authors 2

1. Joëlle Mérgola-Greef Aachen Molecular Biotechnology

   Leiden University · University of Aberdeen

   Affiliation as printed

   Marine Biodiscovery Centre, University of Aberdeen, Meston Walk, Aberdeen, United Kingdom, AB24 3UE

   Molecular Biotechnology, Leiden University, Sylviusweg 72, Leiden, Netherlands, 2333 BE

2. Bruce Forbes Milne

   University of Aberdeen

   Affiliation as printed

   Marine Biodiscovery Centre, University of Aberdeen, Meston Walk, Aberdeen, United Kingdom, AB24 3UE