Membrane Permeability of Cyclic and Linear Peptides, a Halogenated Anti-Sickling Molecule, and Water Across a Red Blood Cell Bilayer Model

We studied through molecular dynamics and inhomogeneous solubility-diffusion theory, the permeability of several cyclic peptides (CPs) recently proposed as potential anti-sickling drugs, across a red blood cell (RBC) membrane model. The permeability of the CPs is compared to that of a linear precursor, a highly charged CP, a high permeability halogenated anti-sickling molecule (PD150606), and water. The influence of cholesterol (45% of the membrane) is assessed through comparison with the permeability across a homogenous lipid bilayer. The most promising CPs concerning their potential anti-sickling activity depict the highest permeabilities, only exceeded by PD150606. The permeability of a hydrophobic CP is four decades higher than its linear precursor despite non-covalent cyclization in the interior of the membrane. Further, cholesterol is found to significantly reduce the permeability of water and a model CP, while not influencing that of PD150606. The influence of the water model is also investigated.