Effects of Trehalose on Lipid Membranes under Rapid Cooling using All-Atom and Coarse-Grained Molecular Simulations

We investigate the effect of the cryopreservative α-α-trehalose on a model 1,2-dimyristoyl-sn-glycero-3-phosphocholine (DMPC) lipid membrane undergoing cooling from 350 to 250 K using all-atom (AA) and coarse-grained (CG) molecular dynamics simulation. In the AA simulations, we find that the addition of trehalose alters the Lα (liquid crystalline) to Pβ (ripple) phase transition, suppressing the major domain of the Pβ phase and increasing the degree of leaflet interdigitation (the minor domain) which yields a thinner membrane with a higher area per lipid. Calculation of dihedral angle distributions for the lipid tails shows a greater fraction of gauche angles in the Pβ phase as trehalose concentration is increased, indicating that trehalose increases lipid disorder in the membrane. In contrast, the CG simulations transition directly from the Lα to the Lβ (gel) phase upon cooling without exhibiting the Pβ phase (likely due to increased lipid mobility in the CG system). Even so, the CG simulations show that the addition of trehalose clearly suppresses the Lα to Lβ phase transition, demonstrating that trehalose increases lipid disorder at low temperatures for the CG system, similar to the AA. Analysis using a two-state binding model provides net affinity coefficients between trehalose and the membrane as well as trehalose partition coefficients between the membrane interface and the bulk solution for both the AA and CG systems.