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

Abstract

We studied through molecular dynamics and inhomogeneous solubility-diffusion theory the permeability of several cyclic peptides (CPs) recently proposed as potential antisickling 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 antisickling molecule (PD150606), and water. The influence of cholesterol (45% of the membrane) is assessed through comparison with the permeability across a homogeneous lipid bilayer. The most promising CPs concerning their potential antisickling activity depict the highest permeabilities, only exceeded by PD150606. The permeability of a hydrophobic CP is four decades higher than its linear precursor despite noncovalent 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.