Helix perturbations in membrane proteins assist in inter-helical interactions and optimal helix positioning in the bilayer

Transmembrane (TM) helices in integral membrane proteins are primarily alpha-helical in structure. Here we analyze 1134 TM helices in 90 high resolution membrane proteins and find that apart from the widely prevalent alpha-helices, TM regions also contain stretches of 3(10) (3 to 8 residues) and pi-helices (5 to 19 residues) with distinct sequence signatures. The various helix perturbations in TM regions comprise of helices with kinked geometry, as well as those with an interspersed 3(10)/pi-helical fragment and show high occurrence in a few membrane proteins. Proline is frequently present at sites of these perturbations, but it is neither a necessary nor a sufficient requirement. Helix perturbations are also conserved within a family of membrane proteins despite low sequence identity in the perturbed region. Furthermore, a perturbation influences the geometry of the TM helix, mediates inter-helical interactions within and across protein chains and avoids hydrophobic mismatch of the helix termini with the bilayer. An analysis of pi-helices in the TM regions of the heme copper oxidase superfamily shows that interspersed pi-helices can vary in length from 6 to 19 amino acids or be entirely absent, depending upon the protein function. The results presented here would be helpful for prediction of 31,3 and pi-helices in TM regions and can assist the computational design of membrane proteins. (C) 2016 Published by Elsevier B.V.