Fatty Acyl Chains

Lipid fatty acyl chain lengths determine the hydrophobic thickness of a lipid bilayer. The hydrophobic thickness of a lipid bilayer is expected to match well the hydrophobic thickness of any protein embedded in the bilayer, because of the high cost of exposing either fatty acyl chains or hydrophobic amino acids to water. The efficiency of hydrophobic matching has been demonstrated experimentally for the potassium channel KcsA where varying the chain length for the surrounding phospholipids from C12 to C24 results in no change in the environment of the Trp residues located at the ends of the transmembrane a-helices (Williamson et al. 2002). Any mismatch between the hydrophobic thicknesses of the lipid bilayer and the protein would be expected to lead to distortion of the lipid bilayer, or the protein, or both, to minimize the mismatch.

The energetics of distortion of the lipid bilayer have been analysed in terms of the bulk bending properties of the lipid bilayer described above, with stretching of the lipid chains being required when the lipid bilayer is too thin and compression when the bilayer is too thick (Fig. 6.10) (Mouritsen and Bloom 1984; Fattal and Ben-Shaul 1993; Nielsen et al. 1998). A comparison of relative lipid binding constants estimated from the results of such a theoretical calculation (Fattal and Ben-Shaul 1993) with experimental data shows that agreement is reasonable for moderate levels of mismatch for the P-barrel protein OmpF but is poor for the a-helical protein MscL (O'Keeffe et al. 2000; Powl et al. 2003) (Fig. 6.11). Presumably, the P-barrel structure of OmpF makes it relatively rigid so that distortion of the lipid bilayer to provide hydrophobic matching is less costly than distortion of the protein. Similarly, the effects of bilayer thickness on the properties of the dimer-channel formed by gramicidin fit well to a model based on elastic deformation of the lipid bilayer around the gramicidin dimer (Lundbaek and Andersen 1999; Nielsen and Andersen 2000) and the presence of gramicidin has been shown to thicken a bilayer of di(C12:0)PC but to compress one of di(C14:0)PC (Harroun et al. 1999). In contrast, an a-helical protein is less rigid, and both distortion of a

Fig. 6.10. Hydrophobic mismatch. The diagram shows how a lipid bilayer could distort around a membrane protein whose hydrophobic thickness was greater than that of the lipid bilayer (left; dp > d|) or less than that of the lipid bilayer (right; dp < d|). (a) shows a side view of the membrane and (b) shows a view down onto the surface of the membrane. When the hydrophobic thickness of the protein is greater than the hydrophobic thickness of the bilayer, the lipid chains must be stretched so that the surface area occupied by a lipid molecule will be less in the vicinity ofthe protein than for bulk lipid. Conversely, to match a protein with a thin transmembrane region the fatty acyl chains of neighbouring lipids will be compressed and will therefore occupy a greater surface area

12 14 16 18 20 22 24

Chain length

Fig. 6.11. The dependence of lipid binding constants on chain length. Binding constants for phosphatidylcholines relative todi(C16:1)PC for MscL (o) and relative to di(C14:1)PC for the |3-barrel protein OmpF (□) are plotted against fatty acyl chain length. The dotted line shows the theoretical dependence of lipid binding constant on chain length calculated from the data of Fattal and Ben-Shaul (1993) for a protein of hydrophobic thickness 30 A, as described in Powl et al. (2003). Data from O'Keeffe et al. (2000) and Powl et al. (2003)

Fig. 6.10. Hydrophobic mismatch. The diagram shows how a lipid bilayer could distort around a membrane protein whose hydrophobic thickness was greater than that of the lipid bilayer (left; dp > d|) or less than that of the lipid bilayer (right; dp < d|). (a) shows a side view of the membrane and (b) shows a view down onto the surface of the membrane. When the hydrophobic thickness of the protein is greater than the hydrophobic thickness of the bilayer, the lipid chains must be stretched so that the surface area occupied by a lipid molecule will be less in the vicinity ofthe protein than for bulk lipid. Conversely, to match a protein with a thin transmembrane region the fatty acyl chains of neighbouring lipids will be compressed and will therefore occupy a greater surface area

the lipid bilayer and distortion of the protein is likely (Lee 2004) because the cost of distorting a lipid bilayer is relativelyhigh (Lundbaek et al. 2004). Distortion of a-helical membrane proteins explains the marked dependence of the activities of a-helical membrane proteins on bilayer thickness (Lee 2004).

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