Robust Driving Forces for Transmembrane Helix Packing

Abstract

The packing structures of transmembrane helices are traditionally attributed to patterns in residues along the contact surface. In this view, besides keeping the helices confined in the membrane, the bilayer has only a minor effect on the helices structure. Here, we use two different approaches to show that the lipid environment has a crucial effect in determining the cross-angle distribution of packed helices. We analyzed structural data of a membrane proteins database. We show that the distribution of cross angles of helix pairs in this database is statistically indistinguishable from the cross-angle distribution of two noninteracting helices imbedded in the membrane. These results suggest that the cross angle is, to a large extent, determined by the tilt angle of the individual helices. We test this hypothesis using molecular simulations of a coarse-grained model that contains no specific residue interactions. These simulations reproduce the same cross-angle distribution as found in the database. As the tilt angle of a helix is dominated by hydrophobic mismatch between the protein and surrounding lipids, our results indicate that hydrophobic mismatch is the dominant factor guiding the transmembrane helix packing. Other short-range forces might then fine-tune the structure to its final configuration.

Lipid mediated packing of transmembrane helices – a dissipative particle dynamics study

“…This increase matches with the previously reported results 14,16 and displays a slope similar to the one observed in natural helices. 26 In super-positive mismatched helices (Dd T 20Å) we observe a change in the slope of tilt angle, as helices tend to adopt a higher tilt angle. This effect has not been observed before as, to the best of our knowledge, this range of hydrophobic mismatches had not been explored previously.…”

“…This effect was previously observed for synthetic peptides, 14,16,19 though it differs signi-cantly from what is observed in natural helices. 26 In synthetic helices, as well as in our current model, the ends of the helix are hydrophilic and so are forced to be in contact with the hydrophilic part of the membrane (or water). In those helices, tilting would decrease the effective hydrophobic size of the helix along the membrane normal, making it energetically unfavorable.…”

“…One can see evidence for that in natural TM helices as well. 26 This suggests a robust mechanism for determining the cross angle between TM helices. The hydrophobic mismatch of a helix in a membrane will determine to a large extent its relative orientation to other helices.…”

Geometric rules of channel gating inferred from computational models of the P2X receptor transmembrane domain

“…The average M2 crossing angles are also decreased as the bilayer thickness increases, being 77.8 • in DLPC (n = 9), 66.5 • in POPC (n = 9) and 62.2 • in SOPC (n = 9). These data suggest that hydrophobic matching is the driving force behind changes in the tilt and crossing angles of M2 helices [1,20,2].…”

Small scale membrane mechanics

“…To test the predictive potential of the continuum model, we compare the tilt angle distributions when proteins are inserted in the membrane using a previously developed CG DPD model (Kranenburg et al 2003; de Meyer et al 2008; Benjamini and Smit 2012). …”