Differential equilibration in <i>cis</i> - and <i>trans</i> -ceramide monolayers: A molecular dynamics study

Ceramides are N-acyl sphingosine derivatives with important functions in cell signaling and skin impermeability. Virtually all unsaturated sphingosines found in nature contain a 4-5 trans double bond. The trans configuration is essential for most ceramide functions. Several laboratories, including our own, have tried to understand the reasons for that configurational specificity. We found that, unlike the trans-isomer, cis-palmitoyl ceramide exhibited a kinetically restricted solid-solid phase transition with unusually large changes of molecular area under isothermal compression and marked hysteresis. We present a computational study of the equilibration properties of monolayers consisting of either cis- or trans-ceramides, using molecular dynamics. A reverse-pathway ordered-start atomistic simulation protocol has been developed, starting simulations from low-energy ordered states with hexagonal tail packing and favorable intermolecular amide group interactions, rather than from disordered states. This allowed for much shorter computational times than the conventional approach. This approach was complemented with virtual compression and expansion processes through sequential rescaling of atomic positions along the surface, followed by energy minimization and molecular dynamics runs. Large-scale atomistic simulations were performed on systems with 3456 lipids (72 × 48 arrays) hydrated with a 40 Å-thick water slab. The main conclusions are that trans-ceramide monolayers adopt an ordered conformation more easily (i.e., within a shorter range of mean areas per lipid) than their cis-counterparts and that the water interactions of the polar heads differ according to the isomer, with cis-ceramides being unable to form an intramolecular H-bond between the two OH groups and being oriented less deeply into water.