Membrane properties of cholesterol analogs with an unbranched aliphatic side chain

• We investigate the membrane properties of synthetic cholesterol analogs with different unbranched aliphatic side chains.
• Side chain length has impact on molecular packing, but only a minor influence on membrane permeation and lateral diffusion.
• The length of an unbranched side chain has a smaller influence on the membrane properties as an iso-branched side chain.
• For the same molecular packing effect as for a sterol with an iso-branched chain, a longer unbranched side chain is needed.

The interactions between cholesterol and other membrane molecules determine important membrane properties. It was shown that even small changes in the molecular structure of cholesterol have a crucial influence on these interactions. We recently reported that in addition to alterations in the tetracyclic ring structure, the iso-branched side chain of cholesterol also has a significant impact on membrane properties ( Scheidt et al., 2013). Here we used synthetic cholesterol analogs to investigate the influence of an unbranched aliphatic side chain of different length. The 2H NMR order parameter of the phospholipid chains and therefore the molecular packing of the phospholipid molecules shows a significant dependence on the sterol’s alkyl side chain length, while, membrane permeation studied by a dithionite ion permeation assay and lateral diffusion measured by 1H MAS pulsed field gradient NMR are less influenced. To achieve the same molecular packing effect similar to that of an iso-branched aliphatic side chain, a longer unbranched side chain (n-dodecyl instead of n-octyl) at C17 of cholesterol is required. Obviously, sterols having a branched iso-alkyl chain with two terminal methyl groups exhibit altered cholesterol–phospholipid interactions compared to analogous molecules with a straight unbranched chain.