Permeation of a Homologous Series of NBD-Labeled Fatty Amines through Lipid Bilayers: A Molecular Dynamics Study

Permeation through biomembranes is ubiquitous for drugs to reach their active sites. Asymmetry of the cell plasma membrane (PM) has been described as having an important role in this process. Here we describe the interaction of a homologous series of 7-nitrobenz-2-oxa-1,3-diazol-4-yl (NBD)-labeled amphiphiles (NBD-Cn, n = 4 to 16) with lipid bilayers of different compositions (1-palmitoyl, 2-oleoyl-sn-glycero-3-phosphocholine (POPC):cholesterol (1:1) and palmitoylated sphingomyelin (SpM):cholesterol (6:4)), including an asymmetric bilayer. Both unrestrained and umbrella sampling (US) simulations (at varying distances to the bilayer center) were carried out. The free energy profile of NBD-Cn at different depths in the membrane was obtained from the US simulations. The behavior of the amphiphiles during the permeation process was described regarding their orientation, chain elongation, and H-bonding to lipid and water molecules. Permeability coefficients were also calculated for the different amphiphiles of the series, using the inhomogeneous solubility-diffusion model (ISDM). Quantitative agreement with values obtained from kinetic modeling of the permeation process could not be obtained. However, for the longer, and more hydrophobic amphiphiles, the variation trend along the homologous series was qualitatively better matched by the ISDM when the equilibrium location of each amphiphile was taken as reference (& UDelta;G = 0), compared to the usual choice of bulk water.

Automated summary

Permeation through biomembranes is crucial for drugs to reach their targets, and the asymmetry of cell plasma membrane plays an important role in this process. This study investigates the interaction of a series of NBD-labeled amphiphiles with lipid bilayers of different compositions, including an asymmetric bilayer. The behavior of the amphiphiles during permeation, including their orientation, chain elongation, and H-bonding, is described. The permeability coefficients of the amphiphiles are also calculated, but quantitative agreement with experimental values could not be achieved.