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. 2005 May;88(5):3083-94.
doi: 10.1529/biophysj.104.053769. Epub 2005 Feb 18.

Structure and dynamics of model pore insertion into a membrane

Carlos F Lopez  1 , Steve O Nielsen, Bernd Ensing, Preston B Moore, Michael L Klein
Affiliations

Structure and dynamics of model pore insertion into a membrane

Carlos F Lopez et al. Biophys J. 2005 May.

Abstract

A cylindrical transmembrane molecule is constructed by linking hydrophobic sites selected from a coarse grain model. The resulting hollow tube assembly serves as a representation of a transmembrane channel, pore, or a carbon nanotube. The interactions of a coarse grain di-myristoyl-phosphatidyl-choline hydrated bilayer with both a purely hydrophobic tube and a tube with hydrophilic caps are studied. The hydrophobic tube rotates in the membrane and becomes blocked by lipid tails after a few tens of nanoseconds. The hydrophilic sites of the capped tube stabilize it by anchoring the tube in the lipid headgroup/water interfacial region of each membrane leaflet. The capped tube remains free of lipid tails. The capped tube spontaneously conducts coarse grain water sites; the free-energy profile of this process is calculated using three different methods and is compared to the barrier for water permeation through the lipid bilayer. Spontaneous tube insertion into an undisturbed lipid bilayer is also studied, which we reported briefly in a previous publication. The hydrophobic tube submerges into the membrane core in a carpetlike manner. The capped tube laterally fuses with the closest leaflet, and then, after plunging into the membrane interior, rotates to assume a transbilayer orientation. Two lipids become trapped at the end of the tube as it penetrates the membrane. The hydrophilic headgroups of these lipids associate with the lower tube cap and assist the tube in crossing the interior of the membrane. When the rotation is complete these lipids detach from the tube caps and fuse with the lower leaflet lipids.

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Figures

FIGURE 1
FIGURE 1
Comparison of coarse-grain and all-atom representations of the lipid DMPC.
FIGURE 2
FIGURE 2
Comparison of a purely HBT (panel A) and an HBTC (panel B). Hydrophobic sites are shown in purple and hydrophilic sites in red.
FIGURE 3
FIGURE 3
Mean forces of constraint from the 40 constrained runs of 4.5 μs each. Error bars are assigned from the standard deviation of the mean in each of 20 consecutive 225-ns windows. The constraint is imposed by tethering the reaction coordinate to a fixed value with a harmonic spring of stiffness of 13,800 pN/Å (831 kJ/mol/Å2). A cubic spline is fit to the data as shown to calculate the integral. Note that 600 K = 5.0 kJ/mol.
FIGURE 4
FIGURE 4
Snapshots of an HBT (purple) in a cgDMPC bilayer as Ws (blue) passes across the HBT (panel A) and after a lipid tail (yellow) blocks the HBT (panel B). Choline is shown in red, phosphate in purple and the phosphate and glycerol in dark blue.
FIGURE 5
FIGURE 5
Oscillations of the tilt angle of the tube long axis with respect to the bilayer normal for HBT (top: run 1A) and HBTC (bottom: run 1B) embedded in a cgDMPC bilayer. The corresponding time accumulated histograms of the angles are embedded in each graph.
FIGURE 6
FIGURE 6
Density profile of the lipid (line) water (dot-dash) and HBTC tube (dash) for simulation 1B. The tube remains anchored at the lipid water interface throughout the run.
FIGURE 7
FIGURE 7
Snapshot of water (blue) diffusing across the HBTC tube embedded in a cgDMPC bilayer. The hydrophobic part of the tube is depicted in purple, and the hydrophilic caps in red. The lipid tails (yellow), phosphate unit (purple), choline unit (red), and glycerol and ester groups (dark blue) are shown semitransparent.
FIGURE 8
FIGURE 8
Voronoi diagram for the tube atoms and lipid centers of mass for one leaflet snapshot halfway through simulation 1B. The tube points (•) and lipid points (○) are shown for each polygon. The first lipid shell (cyan) and second shell (orange) have a different packing as discussed in the text.
FIGURE 9
FIGURE 9
Free energy of water in the tube calculated with three different methods: constrained MD, equilibrium simulations, and steered MD (see the text for details). The solid circles indicate the average positions of the eight rings of the tube. Only relative energies are meaningful: the absolute scale is arbitrary. Note that 1000 K = 8.3 kJ/mol.
FIGURE 10
FIGURE 10
Distribution of work values for different pulling speeds at a vertical distance from the tube center of 5 Å, starting from an equilibrium distribution constrained at a vertical distance from the tube center of −2 Å. Notice that the distribution corresponding to the fastest pulling speed is non-Gaussian. The distributions have all been scaled so that their maximum value is assigned a probability density of one. Note that 1000 K = 8.3 kJ/mol.
FIGURE 11
FIGURE 11
Free energy of water in the tube estimated with 10 steered MD simulations at a constant velocity of 0.05 Å/ns. The overlap of the second order and full exponential estimates indicates that the distribution of work values is Gaussian. Note that 1000 K = 8.3 kJ/mol.
FIGURE 12
FIGURE 12
Free energy of water in the tube estimated with 100 steered MD simulations at a constant velocity of 0.5 Å/ns. Note that 1000 K = 8.3 kJ/mol.
FIGURE 13
FIGURE 13
Free energy of water in the tube estimated with 1000 steered MD simulations at a constant velocity of 5 Å/ns. Note that 1000 K = 8.3 kJ/mol.
FIGURE 14
FIGURE 14
Illustrative snapshot of the HBT submerged in the hydrophobic core of the membrane after spontaneous insertion in run 2A.
FIGURE 15
FIGURE 15
Snapshots (left) and Voronoi diagrams (right) for the evolution of the insertion and rotation of the HBTC into the bilayer (simulation 2B). The Voronoi diagrams on the right depicting the first (cyan) and second (orange) solvation shells are shown. The color scheme for the snapshots is the same as in Fig. 7.
FIGURE 16
FIGURE 16
Evolution of the density profile of the lipid (line), water (dot-dash), and HBTC tube (dash) system as HBTC submerges and rotates into a cgDMPC lipid bilayer (simulation 2B).
FIGURE 17
FIGURE 17
Evolution of the tilt angle between the long axis of HBTC and the bilayer normal throughout HBTC insertion (simulation 2B). The tube begins parallel to the bilayer plane and rotates to become perpendicular to the bilayer plane in a transmembrane conformation. The inset shows the normalized angle histograms.
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