Abstract
Conformational ensembles of eight cyclic hexapeptide diastereomers in explicit cyclohexane, chloroform, and water were analyzed by multicanonical molecular dynamics (McMD) simulations. Free-energy landscapes (FELs) for each compound and solvent were obtained from the molecular shapes and principal component analysis at T = 300 K; detailed analysis of the conformational ensembles and flexibility of the FELs revealed that permeable compounds have different structural profiles even for a single stereoisomeric change. The average solvent-accessible surface area (SASA) in cyclohexane showed excellent correlation with the cell permeability, whereas this correlation was weaker in chloroform. The average SASA in water correlated with the aqueous solubility. The average polar surface area did not correlate with cell permeability in these solvents. A possible strategy for designing permeable cyclic peptides from FELs obtained from McMD simulations is proposed.