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

Abstract

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.

In silico studies of the interactions between propofol and fentanyl using Gaussian accelerated molecular dynamics

“…We initially suspected that this distance was due to the propofol molecules interacting with each other and forming a small cluster, as was observed in our previous work. (Faulkner et al, 2020) Upon further investigation we observe this same distance for subunits S3 and S4 in which only one molecule has stable distances between 10 and 20 Å, which rules out the hypothesise that this is caused by intermolecular interaction. The data shown in Figure 5 were taken from one replicate in which the most interactions were observed.…”

Mechanism of interactions between egg protein–derived tri‐peptides and cellular membrane by molecular dynamic simulation and isothermal titration calorimetry

“…Both thickness and area per lipid of the DPPC bilayer were important properties to assess membrane function and stability (Ravindran et al ., 2020). The average thickness value of the pure membrane was 3.71 nm, which was consistent with the calculated value (Yuan et al ., 2020) (3.68 nm) and the experimental value (3.83 nm) (Khajeh & Modarress, 2014) (Faulkner et al ., 2020). The average membrane thickness values were 4.49, 4.53 and 4.51 nm for the peptides (ADF, FGR and MIR)–membrane system over 400 ns, respectively, which were higher than those of the pure membrane.…”

“…The MSD curves for each peptide–membrane system and pure membrane system were almost linear with respect to time. An increase in the MSD value for three lipid systems was observed, probably because all peptides have a spontaneous diffusion from water phase to membrane surface and occupies the free volume space of the head group region, while they were not fully across the membrane over the whole simulation (Faulkner et al ., 2020). The higher MSD value in the peptide MIR–membrane system indicated that the peptide MIR increased the membrane fluidity and influenced the membrane stability, which was probably because of the strongest interaction of peptide MIR with the membrane in the simulation.…”

Investigating the Permeation Mechanism of Typical Phthalic Acid Esters (PAEs) and Membrane Response Using Molecular Dynamics Simulations

“…Bider et al found that the presence of DEHP in the bilayers will alter membrane properties, like membrane thickness, width, order parameters, and acyl chain orientation [19]. Similar results were observed in some other small molecule-membrane systems, such as butanol [20], thymol [21], propofol, and fentanyl [22]. Given the lipophilicity and low water solubility, we speculate that the adsorption or permeation of PAEs may change the characteristics of the bio-membrane itself, resulting in certain biological damage.…”