Hydrophobic mismatch

Hydrophobic mismatch is the difference between the thicknesses of hydrophobic regions of a transmembrane protein and of the biological membrane it spans. In order to avoid unfavorable exposure of hydrophobic surfaces to water, the hydrophobic regions of transmembrane proteins are expected to have approximately the same thickness as the hydrophobic (lipid acyl chain) region of the surrounding lipid bilayer. Nevertheless, the same membrane protein can be encountered in bilayers of different thickness. In eukaryotic cells, the plasma membrane is thicker than the membranes of the endoplasmic reticulum. Yet all proteins that are abundant in the plasma membrane are initially integrated into the endoplasmic reticulum upon synthesis on ribosomes. Transmembrane peptides or proteins and surrounding lipids can adapt to the hydrophobic mismatch by different means. Hydrophobic mismatch is the difference between the thicknesses of hydrophobic regions of a transmembrane protein and of the biological membrane it spans. In order to avoid unfavorable exposure of hydrophobic surfaces to water, the hydrophobic regions of transmembrane proteins are expected to have approximately the same thickness as the hydrophobic (lipid acyl chain) region of the surrounding lipid bilayer. Nevertheless, the same membrane protein can be encountered in bilayers of different thickness. In eukaryotic cells, the plasma membrane is thicker than the membranes of the endoplasmic reticulum. Yet all proteins that are abundant in the plasma membrane are initially integrated into the endoplasmic reticulum upon synthesis on ribosomes. Transmembrane peptides or proteins and surrounding lipids can adapt to the hydrophobic mismatch by different means. In order to avoid unfavorable exposure of hydrophobic surfaces to a hydrophilic environment, biological membrane tends to make some adaptations to such mismatch. In various other systems, is that an integral protein tends to surround itself by lipids of matching size and shape. Since proteins are relatively rigid, whereas lipid hydrocarbon chains are flexible, the condition of hydrophobic matching can be fulfilled by stretching, squashing, and/or tilting of the lipid chains Since Mouritsen and Bloom proposed the detailed thermodynamic model, which includes adaptation of the lipids and induction of protein segregation at a more extreme mismatch in their “Mattress Model”, more additional insight into mismatch-induced protein aggregation has been obtained. Also some experimental evidence that a hydrophobic mismatch can lead to protein aggregation in fluid bilayer were founded. Electron microscopy studies on bacteriorhodopsin, reconstituted in saturated and unsaturated fluid PC bilayers with varying chain length, showed that protein aggregation occurred only with a rather large mismatch, and that bilayer thicknesses of 4 angstrom thicker and 10 angstrom thinner than the estimated hydrophobic thickness of the protein are allowed without induction of significant aggregation. Tilt is also a possible result if the hydrophobic part of a peptide or protein is too long to span the membrane. A previous study on lactose permease of E. coli showed that upon reconstitution of the protein in PE/PG (3/1) lipid bilayer, an increase in helix tilt occurs at increasing protein content. This tilt was accompanied by a decrease in lipid order, which results in a decrease in bilayer thickness, suggesting that it is a mismatch related response. In large proteins that span the membrane multiple times, changes in helical tilt may occur with little effect on lipid packing. However, for a single transmembrane helix, it is possible that a tilt would cause a strain on the surrounding lipids to accommodate the helix in the bilayer. Thus, a large degree of tilting can be a less favorable option for single transmembrane proteins. Relatively small hydrophobic peptides may not be able to integrate into the membrane, and in response adopt an orientation at the membrane surface. The experimental evidence was shown by a fluorescence study on an artificial peptide with a 19 amino acid long hydrophobic sequence of mainly leucines and flanked on both sides with lysines as anchoring residues. The results indicated that a conversion from a dominant transmembrane to parallel orientation of the peptide could be induced by modulating bilayer thickness via addition of cholesterol or by increasing lipid chain length.