Lipid bilayer pressure profiles and mechanosensitive channel gating

Abstract

The function of membrane proteins often depends on the proteins' interaction with their lipid environment, spectacularly so in the case of mechanosensitive channels, which are gated through tension mediated by the surrounding lipids. Lipid bilayer tension is distributed quite inhomogeneously, but neither the scale at which relevant variation takes place nor the effect of varying lipid composition or tension has yet been investigated in atomic detail. We calculated lateral pressure profile distributions in lipid bilayers of various composition from all-atom molecular dynamics simulations totaling 110.5 ns in length. Reproducible pressure profile features at the 1 A length scale were determined. Lipids with phosphatidylcholine headgroups were found to shift the lateral pressure out of the hydrophobic core and into the headgroup region by an amount that is independent of area per lipid. POPE bilayers simulated at areas smaller than optimal exerted dramatically higher lateral pressure in a narrow region at the start of the aliphatic chain. Stretching of POPC bilayers increased tension predominantly in the same region. A simple geometric analysis for the gating of the mechanosensitive channel MscL suggests that pressure profiles affect its gating through the second moment of the profile in a tension-independent manner.

FIGURE 1

Effect of pressure profile discretization for DLPE. (Solid line) Simulation A1, computed with 60 bins of thickness 1.09 Å. (Dashed line) Simulation A2, computed with 120 bins of thickness 0.55 Å.

FIGURE 2

Pressure profile analysis of POPC membrane from simulation D1. (a) Bonded and kinetic component (solid line) and nonbonded component (dashed line) of the total pressure profile; (b) autocorrelation time of bonded and kinetic component (solid line) and nonbonded component (dashed line); (c) total pressure profile (thick line), bracketed by one standard deviation (thin solid lines).

FIGURE 3

Comparison of DLPE (solid line) and DLPC (dashed line) bilayers. (a) Lipid order parameter. (b) Pressure profile from simulations A1 (DLPE) and B (DLPC). Data are smoothed using a five-point running average. (c) Difference between A1 and B in part b.

FIGURE 4

Comparison of POPC from simulation D1 (64 Ų/lipid) and POPE from simulations C3 and C4 (59 and 64 Ų/lipid, respectively). (a) Lipid order parameters for simulations D1 (circles), C3 (diamonds) and C4 (triangles). (b) Pressure profile for simulation D1 (thick solid line), C3 (dashed line), and C4 (thin solid line). Data are smoothed using a five-point running average. (c) Difference between POPE and POPC pressure profiles. Dashed line, C3–D1; solid line, C4–D1.

FIGURE 5

Effect of stretching a POPE bilayer. Black, simulation C1; red, C2; green, C3; blue, C4. (a) Lipid order parameter for simulations C1–C4. (b) Pressure profiles for simulations C1–C4. Data have been smoothed using a five-point running average. (c) Difference in pressure profile between simulations C2–C4 and simulation C1, using the smoothed data from part b.

FIGURE 6

Effect of stretching a POPC bilayer. Black, simulation D1; red, D2; green, D3; blue, D4. (a) Lipid order parameter for simulations D1–D4. (b) Pressure profiles for simulations D1–D4. Data have been smoothed using a five-point running average. (c) Difference in pressure profile between simulations D2–D4 and simulation D1, using the smoothed data from part b.

FIGURE 7

(a) Mechanosensitive channel MscL from Mycobacterium tuberculosis (Chang et al., 1998) superimposed on a snapshot from POPC membrane simulation D1 (see Table 1). Left, distribution of water (blue), lipid acyl chains (cyan), phosphate atoms (yellow), and ester oxygens (green). Right, pressure profile calculated from simulation D1. Regions of positive surface tension are colored red, negative tension is colored blue, and zero tension is colored white. (b) Time-averaged mass density from simulation D1, relative to bulk water density. Black, total density; yellow, phosphate atom density; green, ester oxygen density; cyan, lipid density; blue, water density. (c) Pressure profile from simulation D1, smoothed using a five-point running average. The net area under the pressure profile curve is nonzero due to the finite surface tension present in the system.

FIGURE 8

Effect of multiple time-stepping algorithm on calculated pressure profiles for simulations D1 (thick solid line), R-D1 (thin solid line), and R2-D1 (dashed line). (a) Lipid order parameter; (b) pressure profile, smoothed using a five-point running average.

FIGURE 9

Analysis of pressure profile interaction with MscL conformational changes. (a) The protein is represented as a truncated cone with radius r(z) and slope s interacting with a pressure profile p(z). (b) Closed form of MscL from an E. coli homology model (Sukharev et al., 2001) at the start of the steered MD simulation of Gullingsrud and Schulten (2003). (c) Open form of MscL at the end of the steered MD simulation of Gullingsrud and Schulten (2003); the cross-sectional area of the channel varies with z.