Interaction of the disaccharides trehalose and gentiobiose with lipid bilayers: a comparative molecular dynamics study.

The disaccharide α,α-trehalose (TRH) is known for its bioprotective action in organisms subject to stressful environmental conditions. However, the mechanisms whereby TRH stabilizes biomolecules remains matter of debate, the five main hypotheses being the water replacement (WRH), headgroup bridging (HBH), vitrification (VIH), water entrapment (WEH) and hydration forces (HFH) hypotheses. Four hypotheses (all except HFH) are in principle compatible with a preferential affinity of the sugar molecules (compared to water) for the biomolecular surface. According to the recently proposed sugar-like mechanism (Pereira and Hünenberger), preferential affinity would result from the entropy gain upon releasing many water molecules from the surface region to the bulk, at the cost of immobilizing and rigidifying fewer sugar molecules. Thus, a more flexible disaccharide such as gentiobiose (GNT) should evidence a weaker preferential affinity, limiting its bioprotective ability. In this work, molecular dynamics (MD) simulations of a dipalmitoyl-phosphatidylcholine (DPPC) bilayer patch in the presence of either pure water or aqueous solutions of GNT or TRH are performed in order to assess the validity of this suggestion. At 475 K and 1.6 m (molal), TRH indeed preserves the bilayer structure to a larger extent compared to GNT. However, the present investigation does not unambiguously indicate which of the above mechanism takes place, since the simulations reveal characteristic features of all of them. This suggests either that multiple mechanisms may be simultaneously active or that their definitions are not precise enough.