Effect of cholesterol on behavior of 5-fluorouracil (5-FU) in a DMPC lipid bilayer, a molecular dynamics study

- Behavior of 5-FU in DMPC/cholesterol membrane was investigated by MD simulations.
- The free energy barriers for translocation of 5-FU were determined by PMF method.
- The 5-FU molecules were accumulated in the vicinity of hydrophilic part of bilayers.
- The minimum and maximum of barriers were independent of cholesterol concentration.
- The 5-FU translocation barrier enhanced with increasing membrane cholesterol.

In this work, molecular dynamics (MD) simulations were performed to investigate the effects of cholesterol on the interaction between the hydrophilic anticancer drug, 5-FU, and fully hydrated 1,2-dimyristoyl-sn-glycero-3-phosphocholine (DMPC) bilayer. Several structural and dynamical parameters of DMPC bilayers with varying amounts of cholesterol (0, 25, and 50 mol%) in the presence and absence of drug molecules were calculated. Moreover, the free energy barriers for translocation of one 5-FU molecule from water to the lipid bilayer were determined by using the potential of mean force (PMF). PMF studies indicated that the location of the maximum free energy barrier was in the hydrophobic middle region of bilayer, while the minimums of the barrier were located at the hydrophilic part of bilayer at the interface with water. The minimum and maximum of the free energy profiles were independent of cholesterol concentration and suggested that the drug molecules 5-FU were accumulated in the vicinity of the polar head group of lipid bilayers. Moreover, the results showed that with increasing cholesterol concentration in the bilayer, the free energy barrier for translocation of 5-FU across the bilayer also increases which can be attributed to the condensing effect of the cholesterol on the bilayer.