Design and Application of Lipophilic Nucleosides as Building Blocks to Obtain Highly Functional Biological Surfaces

For the potential application in nanobiotechnology, we have synthesized three different lipophilic nucleosides and investigated their membrane insertion and localization by solid-state NMR spectroscopy. The hydrophilic headgroups of these nucleosides consist of an adenine or uracil nucleobase, which is attached to a ribose or deoxyribose moiety. The membrane affinity of these molecules is either achieved by the covalent attachment of a 1-octadecynyl chain or an ethisterol moiety. For the first time, the orientation of these molecules and the quantitative localization of their functional groups are measured. All investigated lipophilic nucleosides can be incorporated into phospholipid membranes at high concentration without destroying the lamellar bilayer structure as shown by 31P NMR and 2H NMR. However, the membrane incorporation of the lipophilic nucleosides leads to modifications in the phospholipid packing properties as revealed by 2H NMR on chain-deuterated phospholipids. Although the two nucleosides with the octadecynyl membrane anchor only impose a rather moderate decrease in phospholipid packing density, the nucleoside with a steroid membrane anchor significantly disturbs the lateral organization of the phospholipids in the membrane. Quantitative 1H nuclear Overhauser enhancement spectroscopy under magic angle spinning conditions has been applied to localize the monosaccharide/nucleobase moiety of the nucleoside in the membrane. This method measures the intermolecular interaction strength between molecular segments. For all molecules, a location of the (deoxy)ribose/nucleobase moiety in the lipid−water interface of the membrane has been found that exposes the nucleobase to the aqueous phase, where an interaction with external molecular patterns could take place. These molecules may be useful building blocks to obtain a functionalized membrane surface that can be recognized by complementary nucleic acid strands.