The Effects of Cryosolvents on DOPC−β-Sitosterol Bilayers Determined from Molecular Dynamics Simulations

Abstract

Polyhydroxylated alcohols and DMSO are common cryosolvents that can damage cell membranes at sufficiently high concentrations. The interaction of representative plant cell membranes composed of mixed 1,2-dioleoyl-sn-glycero-3-phosphocholine (DOPC)-β-sitosterol bilayers, at a range of compositions, with a variety of cryosolvent molecules (DMSO, propylene glycol, ethylene glycol, glycerol, and methanol) has been investigated using molecular dynamics simulations. All the cryosolvents cause the bilayers to thin and become disordered; however, DMSO and propylene glycol have a greater disordering effect on the bilayer. Propylene glycol is shown to have the ability to cause the formation of pores in pure DOPC bilayers in a manner similar to that previously shown for DMSO. As the concentration of β-sitosterol within the bilayer increases, the membranes become more resistant to the deleterious effects of the cryosolvents. All three polyhydroxylated species are observed to form hydrogen bonds to multiple phospholipid molecules, effectively acting as cross-linkers, with glycerol being the most effective cross-linker. Increases in the concentration of β-sitosterol reduce overall hydrogen bonding of the bilayer with the cryosolvents as well as cross-linking, with glycerol and ethylene glycol being the most affected. The ability of all of these cryosolvents to affect the integrity of cell membranes appears to be the result of the balance of their ability to disorder lipid bilayers, to diffuse across them, and to interact with the lipid head groups.

On the structure of an aqueous propylene glycol solution

“…In the pharmaceutical industry, propylene glycol is used as a solvent to increase the apparent solubility and the permeation of drugs through lipid membranes [16][17][18][19][20] and as such is used commonly as a co-solvent in oral, intravenous [21][22][23] and topical preparations. 18,24 Interestingly, encapsulating drugs into PG containing liposomes results in a substantial increase in drug-solubility which increases with PG concentration.…”

Molecular Mechanism of the Synergistic Effects of Vitrification Solutions on the Stability of Phospholipid Bilayers

“…Table 2 lists the area of the bilayers in the xy plane and the bilayer thickness (defined as the distance between the peaks in the PL density profiles) for the different systems simulated in this study. For comparison, Table S1, Table S2, Table S3, Table S4, and Table S5 in the Supporting Material show data previously reported (27,30,31) for these bilayers solvated in other solutions but with the simulations performed under the same conditions. In all systems, there is an increase in the area of the bilayer parallel to the plane and a concurrent thinning normal to the plane when compared against the same bilayers solvated in pure water.…”

“…A number of solutions containing a single CPA were simulated, and these systems, as well as others previously simulated under the same conditions (27,30,31), allowed the effect of VS1 on bilayers to be compared against that of single component solutions. The binary systems simulated were DPPC in 2.…”

“…2. DMSO and propylene glycol cause thinning of bilayers to a greater extent than ethylene glycol and glycerol (31,32), resulting in the spontaneous formation of pores at sufficiently high concentration (23,28,31). Even higher concentrations of DMSO will completely destroy bilayers (31,32).…”

“…Polyols are able to form hydrogen bonds to the bilayer and act as cross linkers between multiple PL molecules. This cross-linking ability counteracts to some extent the expansion/thinning effects of polyols, making them less damaging than DMSO (31,32).…”