Partitioning into Colloidal Structures of Fasted State Intestinal Fluid Studied by Molecular Dynamics Simulations

We performed molecular dynamics (MD)
simulations to obtain insights
into the structure and molecular interactions of colloidal structures
present in fasted state intestinal fluid. Drug partitioning and interaction
were studied with a mixed system of the bile salt taurocholate (TCH)
and 1,2-dilinoleoyl-sn-glycero-3-phosphocholine (DLiPC).
Spontaneous aggregation of TCH and DLiPC from unconstrained MD simulations
at the united-atom level using the Berger/Gromos54A7 force fields
demonstrated that intermolecular hydrogen bonding between TCH molecules
was an important factor in determining the overall TCH and DLiPC configuration.
In bilayered systems, these intermolecular hydrogen bonds resulted
in embedded transmembrane TCH clusters. Free energy simulations using
the umbrella sampling technique revealed that the stability of these
transmembrane TCH clusters was superior when they consisted of 3 or
4 TCH per bilayer leaflet. All-atom simulations using the Slipids/GAFF
force fields showed that the TCH embedded in the bilayer decreased
the energy barrier to penetrate the bilayer (ΔGpen) for water, ethanol, and carbamazepine, but not for
the more lipophilic felodipine and danazol. This suggests that diffusion
of hydrophilic to moderately lipophilic molecules through the bilayer
is facilitated by the embedded TCH molecules. However, the effect
of embedded TCH on the overall lipid/water partitioning was significant
for danazol, indicating that the incorporation of TCH plays a crucial
role for the partitioning of lipophilic solutes into e.g. lipidic
vesicles existing in fasted state intestinal fluids. To conclude,
the MD simulations revealed important intermolecular interactions
in lipidic bilayers, both between the bile components themselves and
with the drug molecules.