Atomistic Molecular Dynamics Simulations of Propofol and Fentanyl in Phosphatidylcholine Lipid Bilayers

[Image: see text] Atomistic molecular dynamics (MD) and steered MD simulations in combination with umbrella sampling methodology were utilized to study the general anesthetic propofol and the opioid analgesic fentanyl and their interaction with lipid bilayers, which is not yet fully understood. These molecules were inserted into two different fully hydrated phospholipid bilayers, namely, dioleoylphosphatidylcholine (DOPC) and dipalmitoylphosphatidylcholine (DPPC), to investigate the effects that these drugs have on the bilayer. We determined the role of the lipid chain length and saturation on the behavior of the two drugs. Pure, fully hydrated DOPC and DPPC bilayers were also simulated, and the results were in excellent agreement with the experimental values. Various structural and mechanical properties of each system, such as the area per lipid, area compressibility modulus, order parameter, lateral lipid diffusion, hydrogen bonds, and radial distribution functions, have been calculated to assess how the drug molecules affect the different bilayers. From the calculated results, we show that fentanyl and propofol generally follow similar trends in each bilayer but adopt different favorable positions close to the headgroup/chain interface at the carbonyl groups. Propofol was shown to selectively form hydrogen bonds at the carbonyl carbon in each bilayer, whereas fentanyl interacts with water molecules at the headgroup interface. From the calculated free-energy profiles, we determined that both molecules show a preference for the low-density, low-order acyl chain region of the bilayers and both significantly preferred the DOPC bilayer with propofol and fentanyl having energy minima at −6.66 and −43.07 kcal mol(–1), respectively. This study suggests that different chain lengths and levels of saturation directly affect the properties of these two important molecules, which are seen to work together to control anesthesia in surgical applications.