The role of hydrophobic matching on transmembrane helix packing in cells

Abstract

Folding and packing of membrane proteins are highly influenced by the lipidic component of the membrane. Here, we explore how the hydrophobic mismatch (the difference between the hydrophobic span of a transmembrane protein region and the hydrophobic thickness of the lipid membrane around the protein) influences transmembrane helix packing in a cellular environment. Using a ToxRED assay in Escherichia coli and a Bimolecular Fluorescent Complementation approach in human-derived cells complemented by atomistic molecular dynamics simulations we analyzed the dimerization of Glycophorin A derived transmembrane segments. We concluded that, biological membranes can accommodate transmembrane homo-dimers with a wide range of hydrophobic lengths. Hydrophobic mismatch and its effects on dimerization are found to be considerably weaker than those previously observed in model membranes, or under in vitro conditions, indicating that biological membranes (particularly eukaryotic membranes) can adapt to structural deformations through compensatory mechanisms that emerge from their complex structure and composition to alleviate membrane stress. Results based on atomistic simulations support this view, as they revealed that Glycophorin A dimers remain stable, despite of poor hydrophobic match, using mechanisms based on dimer tilting or local membrane thickness perturbations. Furthermore, hetero-dimers with large length disparity between their monomers are also tolerated in cells, and the conclusions that one can draw are essentially similar to those found with homo-dimers. However, large differences between transmembrane helices length hinder the monomer/dimer equilibrium, confirming that, the hydrophobic mismatch has, nonetheless, biologically relevant effects on helix packing in vivo.

Transmembrane but not soluble helices fold inside the ribosome tunnel

“…The contribution to the overall length of a canonical α-helix per amino acid is 1.5 Å. Therefore, a stretch of ~20 consecutive hydrophobic amino acid residues are required to span the 30 Å of the hydrocarbon core of a ‘typical’ biological membrane 30 . Indeed, the most prevalent length for TM helices is 21 amino acids, according to structure-based statistical analysis 31 .…”

Structure and Dynamics of GPCRs in Lipid Membranes: Physical Principles and Experimental Approaches

“…The adaption of IMP structure to a given hydrophobic mismatch has been extensively studied for low-complexity model IMPs, such as glycophorin A (GpA). These studies show that TMD tilting in response to a hydrophobic mismatch largely preserves inter-TMD interactions (hydrogen bonds and salt bridges), while the overall structure of the IMP is evidently altered [ 64 ]. For GPCRs, studies on the concrete effects of a hydrophobic mismatch are still sparse.…”

Pitfalls of the Martini Model

“…It slightly underestimates the population of the monomeric state. [40][41][42] For completeness, we also performed simulations of polyleucine with the ElNeDyn 34 model and a standard force constant of 500 kJ mol −1 . The number of clusters being present during the 10 µs simulation are shown in Figure S6c Figure S6a.…”