Determination of Functional Group Contributions to Transport through Lipid Bilayers: A Study Using a Hippuric Acid Series
Lloyd, Beatrice B.
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Functional group contributions were determined for six a-methylene substituted phippuric acid compounds across egg lecithin lipid bilayers. These data were compared to results from the analogous series ofp-toluic acid compounds that were carried out using egg Lecithin planar lipid bilayers. Through a vesicular eflux method the rate at which each compound permeated through a large unilamellar vesicle (LUV) was measured. An analysis of this rate versus the pH profile for each compound yielded membrane permeability coefficients (PRX) that varied from 4.5 x 10-4 cm/s for a-methyl p -hippuric acid to 1.06 x 10-8 cm/s for a-carbamoyl p -hippuric acid. These values are greater than three orders of magnitude smaller than their counter parts in the p -toluic acid series, necessitating the use of more stable LUV's rather than planar lipid. Functional group contributions to the free energy oftransfer, MG, from water to the barrier domain derived from the permeability data were determined for the functional groups CI, OCH3, CN, OH, and CONH2 and were found to be 180, 860, 2290, 4020, and 6310 (cal/mol), respectively. These data were compared to those from the a-methyl-substituted p -toluic acid series and exhibited similar behavior. This similarity indicates that the functional group contributions are independent of the molecule to which they are attached. Using the bulk organic solvent/water partition coefficient (KRX) from the toluic acid experiment, the log PRX was plotted against the log KRX to identify which bulk solvent most closely resembles the chemical nature ofthe bilayer barrier for these permeants. The slopes of the plots were, .87, .93, 1.05, and 2.24 for hexadecane/water, hexadecene/water, decadiene/water, and octanol/water, respectively, with the best model solvent being that which yielded a slope closest to unity. These results suggest that the more non-polar solvents are a better model for the barrier domain region of the lipid bilayer, indicating that the barrier domain is more hydrocarbon-like and is probably located in the hydrocarbon-chain region and away from the polar-head region.