Lipid differences between hydrogen-bonding

Most drug-like molecules dissolved in water form hydrogen bonds with the solvent. When such a molecule transfers from water into a phospholipid bilayer, the solute-water hydrogen bonds are broken (desolvation), as new solute-lipid H bonds form in the lipid phase. The free-energy difference between the two states of solvation has direct impact on the ability of the molecules to cross biological barriers. 

Seiler [250] proposed a way of estimating the extent of hydrogen bonding in solute partitioning between water and a lipid phase by measuring the so-called A log P parameter. The latter parameter is usually defined as the difference between the partition coefficient of a solute measured in the octanol-water system and that measured in an inert alkane-water suspension AlogP = log Kp oet — log Kp aik. 

When the ion-pair partitioning is indicated in the quadrant diagram (below) it becomes obvious that a circle of equilibria is present. Knowing the octanol pKa, the log P and the aqueous pKa should allow one to calculate the partition coefficient of the ion pair. From these equilibria one can write that the difference in log P between the acid and its salt is the same as the difference between the pKa s (Equation 9). The closer the pKa s, the more lipid soluble the ion pair will be, relative to the acid. Internal hydrogen bonding or chelation that stabilizes an ion pair will affect the octanol stability more than the aqueous stability, where it is less needed, and so will decrease the delta pKa. Chelation should therefore favor biolipid solubility of ion pairs. Ultimate examples are available in some ionophores. This is one of the properties of some of the herbicides I pointed out earlier. 

Solubility is a function of many molecular parameters. Ionization, molecular structure and size, stereochemistry, and electronic structure all influence the basic interactions between a solvent and solute. As discussed in the previous section, water forms hydrogen bonds with ions or with polar nonionic compounds through -OH, -NH, -SH, and -C=0 groups, or with the nonbonding electron pairs of oxygen or nitrogen atoms. The ion or molecule will thus acquire a hydrate envelope and separate from the bulk solid that is, it dissolves. The interaction of nonpolar compounds with lipids is based on a different phenomenon, the hydrophobic interaction, but the end result is the same formation of a molecular dispersion of the solute in the solvent. 

Quantitative investigation of recognition of this pair of liposomes was performed with isothermal titration microcalorimetry (ITC). It has been found that one-to-one binding between adenine and barbituric acid in the lipid/water/lipid interface occurs. However at T= 58°C, above the main lipid phase transition, the situation is different and no liposomal binding is detected. This is mainly due to the molecular disorder within the bilayer (liquid-disordered/liquid ordered phase coexistence) that limits the capacity of complementary moieties to bind, due to the weakening of the hydrogen bonds at these high temperatures. 

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