A molecular dynamics study of the response of lipid bilayers and monolayers to trehalose

Abstract

Surface tensions evaluated from molecular dynamics simulations of fully hydrated dipalmitoylphosphatidylcholine bilayers and monolayers at surface areas/lipid of 54, 64, and 80 A2 are uniformly lowered 4-8 dyn/cm upon addition of trehalose in a 1:2 trehalose/lipid ratio. Constant surface tension simulations of bilayers yield the complementary result: an increase in surface area consistent with the surface pressure-surface area (pi-A) isotherms. Hydrogen bonding by trehalose, replacement of waters in the headgroup region, and modulation of the dipole potential are all similar in bilayers and monolayers at the same surface area. These results strongly support the assumption that experimental measurements on the interactions of surface active components such as trehalose with monolayers can yield quantitative insight to their effects on bilayers. The simulations also indicate that the 20-30 dyn/cm difference in surface tension of the bilayer leaflet and monolayer arises from differences in the chain regions, not the headgroup/water interfaces.

FIGURE 1

α,α-Trehalose (1,1-α-d-glucopyranosyl α-d-glucopyranoside). Henceforth, this disaccharide is simply denoted trehalose.

FIGURE 2

DPPC bilayer with 40 trehalose from the 20-ns point of NPAT simulation at 64 Ų/lipid. Coloring is as follows: glycosidic oxygen of trehalose, yellow; all other trehalose atoms, orange; phosphate groups of DPPC, green; N(CH₃)₃, purple; carbonyl oxygen, red; all other lipid atoms, gray; waters, transparent blue.

FIGURE 3

DPPC monolayer with 40 trehalose from the 20-ns point from the trajectory at 64 Ų/lipid. Heavy lines indicate the boundaries of the simulation cell, which includes a vacuum/chain interface. Atom coloring is as for Fig. 2.

FIGURE 4

Total density distribution for bilayers (solid curves) and monolayers (dashed curves) with 40 trehalose, the water/trehalose region of the bilayer with 160 trehalose and 6516 water (dotted curve), and a solution of 40 trehalose and 1629 water (thick solid curve). For this and related plots the bilayer and monolayer are placed in same orientation; i.e., with the water in the center (z = 0) and the chains extended toward vacuum for the monolayers and toward the other leaflet for the bilayer. The bilayer midplane (the position of the methyl through) is at z = ±32.95 Å.

FIGURE 5

Electron density distribution of trehalose (thick solid curve), water (solid curve), phosphate (dashed curve), and carbonyl (dotted curve) group from simulations of the bilayer (top) and monolayer (bottom) at 64 Ų/lipid. The dashed vertical lines at z ≈ ±9 Å show the average cutoffs used for trehalose and water counting (see Methods).

FIGURE 6

Time series (1-ns block averages) of surface tension at A = 64 Ų/lipid for the bilayers (top) and monolayers (bottom) of pure DPPC (thick black line), with 40 trehalose (thick gray line), and 160 trehalose (thin black line).

FIGURE 7

Comparison of simulated (○) and experimental surface pressure versus surface area (π-A) isotherms for pure DPPC monolayers. Experimental data at 323 K (×) and 321 K (▴) are from references 35 and 36, respectively. Images of the 20-ns trajectory point for one leaflet of each simulated system are included, with areas 54, 64, and 80 Ų/lipid from left to right.

FIGURE 8

π-A isotherms at 323 K for DPPC monolayers (circles) and bilayers (squares). Pure systems in open symbols; those with 40 trehalose (a 1:2 trehalose/lipid ratio) in solid symbols. SE is comparable to the size of the symbols; lines are included to guide the eye.

FIGURE 9

Time series (500-ps block averages) of water and trehalose binding based on the dividing surface described in Methods and illustrated in Fig. 5. Bilayer (thick black line), monolayer (thick gray line), and 160 trehalose (thin black line) systems are shown at A = 64 Ų/lipid.

FIGURE 10

Dipole potential for lipids (solid curves), water (dashed curves), trehalose (dotted curve), and total (thick solid curves). The center of the water layer is at z = 0 for both bilayers and monolayers.

FIGURE 11

Detail from Fig. 4 of the chain methyl regions of the bilayer (solid line) and monolayer (dashed line). The bilayer midplane is at z = ±32.95 Å.

FIGURE 12

Trajectories of NPγT simulations of pure bilayers (black lines) and bilayers with trehalose (gray lines) at applied surface tensions of 0, 10, 17, and 25 dyn/cm. Points are 5-ps averages.

FIGURE 13

Surface tension-surface area isotherms at 323 K for pure DPPC (top, circles) and DPPC with 40 trehalose (bottom, squares). Simulations carried out at NPAT in open symbols; those at NPγT in solid symbols. SE is comparable to the size of the symbols.