Self-consistent-field modeling of complex molecules with united atom detail in inhomogeneous systems. Cyclic and branched foreign molecules in dimyristoylphosphatidylcholine membranes

We have developed a detailed self-consistent-field model for studying complex molecules in inhomogeneous systems, in which all the molecules are represented in a detailed united atom description. The theory is in the spirit of the approach developed by Scheutjens and co-workers for polymers at interfaces and self-assembly of surfactants and lipids into association colloids. It is applied to lipid membranes composed of dimyristoylphosphatidylcholine (DMPC). In particular, we looked at the incorporation of linear, branched, and cyclic molecules into the lipid bilayers being in the liquid phase. Detailed information on the properties of both the lipids and the additives is presented. For the classes of linear and branched alcohols and phenol derivatives we find good correspondence between calculated partition coefficients for DMPC membranes and experimental data on egg-yolk PC. The calculated partitioning of molecules of isomers, containing a benzene ring, two charged groups (one positive and one negative) and 16 hydrocarbon segments, into DMPC membranes showed variations of the partition coefficient by a factor of 10 depending on the molecular architecture. For zwitterionic additives we find that it is much more difficult to bring the positive charge into the membrane core than the negative one. This result can be rationalized from information on the electrostatic potential profile of the bare membrane, being positive in both the core and on the membrane surface but negative near the position of the phosphate groups. For several tetrahydroxy naftalenes we found that, although the partition coefficient is barely influenced, the average orientation and position of the molecule inside the membrane is strongly dependent on the distribution of the hydroxyl groups on the naphthalene rings. The orientation changes from one where the additive spans the membrane when the hydroxyls are positioned on (2,3,6,7) positions, to an orientation with the rings parallel to the membrane surface and located near the head group–hydrophobic core interface for the hydroxyls at the (1,3,5,7) positions. We propose that, when our model is used in combination with octanol/water partitioning data, a very accurate prediction is possible of the affinity of complex molecules for lipid membranes.