Canonical Azimuthal Rotations and Flanking Residues Constrain the Orientation of Transmembrane Helices

Abstract

In biological membranes the alignment of embedded proteins provides crucial structural information. The transmembrane (TM) parts have well-defined secondary structures, in most cases α-helices and their orientation is given by a tilt angle and an azimuthal rotation angle around the main axis. The tilt angle is readily visualized and has been found to be functionally relevant. However, there exist no general concepts on the corresponding azimuthal rotation. Here, we show that TM helices prefer discrete rotation angles. They arise from a combination of intrinsic properties of the helix geometry plus the influence of the position and type of flanking residues at both ends of the hydrophobic core. The helical geometry gives rise to canonical azimuthal angles for which the side chains of residues from the two ends of the TM helix tend to have maximum or minimum immersion within the membrane. This affects the preferential position of residues that fall near hydrophobic/polar interfaces of the membrane, depending on their hydrophobicity and capacity to form specific anchoring interactions. On this basis, we can explain the orientation and dynamics of TM helices and make accurate predictions, which correspond well to the experimental values of several model peptides (including dimers), and TM segments of polytopic membrane proteins.

Comparisons of Interfacial Phe, Tyr, and Trp Residues as Determinants of Orientation and Dynamics for GWALP Transmembrane Peptides

“…Recently, 23 a method was presented for correlating helix rotational preference with flanking residue positions on a tilted transmembrane helix. We have applied this method to W 18 GWALP23 (Figure 7 ) as well as to the parent GWALP23 helix (Figure 8 ).…”

“…For the analysis of helix rotation, we analyzed some pairwise residue separation distances using a recently described procedure. 23 Distances were compared to hydrophobic thicknesses of 20.9 Å for DLPC 24 and 27.2 Å for DOPC, 25 which are based on the location D C of the Gibbs dividing surface for the hydrocarbon region of the bilayer. 25 …”

Single Tryptophan and Tyrosine Comparisons in the N-Terminal and C-Terminal Interface Regions of Transmembrane GWALP Peptides

“…It has furthermore been suggested that the lipid thickness, helix geometry and immersion depths of individual residues impose constraints for the rotation preferences 43 .…”

“…We note also that the azimuthal rotation preference changes systematically with the identity and thickness of the host lipid (Table ), although as noted above, the differences with respect to anchor group identity (W or Y) and location (position 5 or 19) remain similar in each of the lipids. It has, furthermore, been suggested that the lipid thickness, helix geometry, and immersion depths of individual residues impose constraints for the rotation preferences …”

“…It has, furthermore, been suggested that the lipid thickness, helix geometry, and immersion depths of individual residues impose constraints for the rotation preferences. 43 One can imagine a scenario in which each interfacial aromatic residue is independently trying to influence the helix orientation, and thereby best position itself with respect to the lipid head groups and aqueous interface, so as to enhance its own hydrogen-bonding capabilities. A resulting competition could lead to the dynamic averaging observed with previous WALP peptides that have multiple aromatic groups, each attempting to achieve a favorable location at the bilayer interface.…”