Orientation and dynamics of transmembrane peptides: the power of simple models

Abstract

In this review we discuss recent insights obtained from well-characterized model systems into the factors that determine the orientation and tilt angles of transmembrane peptides in lipid bilayers. We will compare tilt angles of synthetic peptides with those of natural peptides and proteins, and we will discuss how tilt can be modulated by hydrophobic mismatch between the thickness of the bilayer and the length of the membrane spanning part of the peptide or protein. In particular, we will focus on results obtained on tryptophan-flanked model peptides (WALP peptides) as a case study to illustrate possible consequences of hydrophobic mismatch in molecular detail and to highlight the importance of peptide dynamics for the experimental determination of tilt angles. We will conclude with discussing some future prospects and challenges concerning the use of simple peptide/lipid model systems as a tool to understand membrane structure and function.

Fig. 1

Structures of a the transmembrane parts of the potassium channel KscA (PDB entry 1J95) and b the transmembrane model peptide WALP23, which is used to mimic transmembrane segments of membrane proteins. Only tryptophans are shown with explicit side chains, illustrating the belt of aromatic residues present in the tetrameric KcsA

Fig. 2

Schematic representation of possible adaptations in case of a too long transmembrane segment, i.e., positive hydrophobic mismatch conditions: a helix tilting, b acyl chain stretching, c oligomerization, d backbone deformation/distortion, e backbone kinking/flexing, f switching to a non-transmembrane state, i.e., binding to the membrane interface

Fig. 3

a The quasi-static model describes the orientation of the peptide by a tilt angle τ and a rotation angle ρ, with limited motional averaging described by a global order parameter S. b In the dynamic model, the previous model is extended by an oscillation Δρ around the helix axis and by a wobbling-in-a-cone motion Δτ