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. 2012 Oct 17;103(8):1698-705.
doi: 10.1016/j.bpj.2012.08.059. Epub 2012 Oct 16.

Design of peptide-membrane interactions to modulate single-file water transport through modified gramicidin channels

Guillem Portella  1 , Tanja Polupanow, Florian Zocher, Danila A Boytsov, Peter Pohl, Ulf Diederichsen, Bert L de Groot
Affiliations

Design of peptide-membrane interactions to modulate single-file water transport through modified gramicidin channels

Guillem Portella et al. Biophys J. .

Abstract

Water permeability through single-file channels is affected by intrinsic factors such as their size and polarity and by external determinants like their lipid environment in the membrane. Previous computational studies revealed that the obstruction of the channel by lipid headgroups can be long-lived, in the range of nanoseconds, and that pore-length-matching membrane mimetics could speed up water permeability. To test the hypothesis of lipid-channel interactions modulating channel permeability, we designed different gramicidin A derivatives with attached acyl chains. By combining extensive molecular-dynamics simulations and single-channel water permeation measurements, we show that by tuning lipid-channel interactions, these modifications reduce the presence of lipid headgroups in the pore, which leads to a clear and selective increase in their water permeability.

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Figures

Figure 1
Figure 1
(A) Different gramicidin derivatives used in this study: Rn indicates residues and n the position in the sequence. (B) Top and side view of the corresponding molecular models extracted from our MD simulations. Only one monomer is displayed; hydrogen atoms were omitted for clarity. (C) Typical simulation box, showing a peptide (spheres) embedded in a hydrated DMPC bilayer (lipid tails as lines, lipid headgroups as spheres, water molecules as sticks).
Figure 2
Figure 2
(A) Radial density profile from the pore main axis for DMPC lipids (straight) and the peptidic channels (dash), color-coded according to the derivative (left panel). All the atoms contribute to the density estimate. (Insets) Region corresponding to the pore lumen (B), where the occlusion takes place, and the shift in the first density maxima for the acyl-derivatives with respect to gA (C). In panels B and C, we show the standard error of the lipid density, omitted from panel A for clarity. On the right-hand side of the panel, the images show the peptidic channels surrounded by their lipid density isosurface of 0.5 atoms/nm3.
Figure 3
Figure 3
(A) Averaged fraction of time that the channels are blocked by ETA and lipid headgroups. (B) Mean duration time of the channels with at least one open pore entrance. (C) Normalized probability distribution of the number of lipids on the channel (both pore entrances). (D) Example of the time-dependent opening probability of the gA and gA_4 channels, showing a reduced number of transitions to the occluded state for the modified derivative. The data is extracted from a concatenated trajectory of 500 ns in total.
Figure 4
Figure 4
(A) Osmotic permeability coefficients pf for gA and its acylated derivatives experimentally determined by scanning electrochemical microscopy carried out in combination with voltage-clamp experiments and extracted from MD simulations. (B and C) Single-channel potassium conductance and the channel lifetime of the derivatives.
Figure 5
Figure 5
Hydrogen-bond energy per water molecule along the main pore axis (black curve) and its components: water-water (triangles), water-peptide (spheres), and water-lipid (squares). (Gray vertical lines) Pore entrance. (Bar graph) Hydrogen-bond binding energies at the entrance of the channel with respect to the bulk. (Error bars) Standard error of the mean value.
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