A comparative study on the ability of two implicit solvent lipid models to predict transmembrane helix tilt angles

Abstract

Free-energy profiles describing the relative orientation of membrane proteins along predefined coordinates can be efficiently calculated by means of umbrella simulations. Such simulations generate reliable orientational distributions but are difficult to converge because of the very long equilibration times of the solvent and the lipid bilayer in explicit representation. Two implicit lipid membrane models are here applied in combination with the umbrella sampling strategy to the simulation of the transmembrane (TM) helical segment from virus protein U (Vpu). The models are used to study both orientation and energetics of this α-helical peptide as a function of hydrophobic mismatch. We observe that increasing the degree of positive hydrophobic mismatch increased the tilt angle of Vpu. These findings agree well with experimental data and as such validate the solvation models used in this study.

Fig. 1

Protein reorientation in response to hydrophobic mismatch. Schematic representation of the tilting of a TM protein under conditions of hydrophobic mismatch when membrane thickness (D) is smaller than the length of the helix (L). In response to mismatch, the helix tilts relative to the normal of the membrane (here the z direction) such that hydrophobic side chains are buried inside the membrane

Fig. 2

Tilt angle time series. Tilt angles are shown as a function of time for Vpu simulated in the IMM1 (a) and GBSW (b) implicit membrane models. Results are shown for simulations where D (membrane thickness) is 15 (black), 19 (blue), 23 (green), and 27 Å (red). Shown on each plot are the average angles. For comparison, experimental tilt angles are shown in parentheses. Shown in (c) is a plot of cos(θ) vs. D determined using results from IMM1 simulation (red), GBSW (black) simulation, and experiment (blue) (Color figure online)

Fig. 3

Potential of mean force profiles. Free-energy profiles are shown as a function of tilt angle (θ) calculated using the IMM1 (a) and GBSW (b) implicit membrane models. Shown are profiles calculated where D (membrane thickness) is 15 (black), 19 (blue), 23 (green), and 27 Å (red) (Color figure online)