title: Propofol modulates the lipid phase transition and localizes near the headgroup of membranes.
abstract: The compound 2,6-diisopropylphenol (Propofol, PRF) is widely used for inducing general anesthesia, but the mechanism of PRF action remains relatively poorly understood at the molecular level. This work examines the possibility that a potential mode of action of PRF is to modulate the lipid order in target membranes. The effect on monolayers and bilayers of dipalmitoyl-sn-glycero-3-phosphorylcholine (DPPC) was probed using Langmuir monolayer isotherms, differential scanning calorimetry (DSC), isothermal titration calorimetry (ITC) and molecular dynamics (MD) simulations. Increasing amounts of PRF in a DPPC monolayer causes a decrease in isothermal compressibility modulus at the phase transition. A partition constant for PRF in DPPC liposomes on the order of K≈1500 M(-1) was found, and the partitioning was found to be enthalpy-driven above the melting temperature (Tm). A decrease in Tm with PRF content was found whereas the bilayer melting enthalpy ΔHm remains almost constant. The last finding indicates that PRF incorporates into the membrane at a depth near the phosphatidylcholine headgroup, in agreement with our MD-simulations. The simulations also reveal that PRF partitions into the membrane on a timescale of 0.5 μs and has a cholesterol-like ordering effect on DPPC in the fluid phase. The vertical location of the PRF binding site in a bacterial ligand-gated ion channel coincides with the location found in our MD-simulations. Our results suggest that multiple physicochemical mechanisms may determine anesthetic potency of PRF, including effects on proteins that are mediated through the bilayer.
authors.affiliation: MEMPHYS - Center for Biomembrane Physics, Department of Physics, Chemistry and Pharmacy, University of Southern Denmark, 5230 Odense M, Denmark.
authors.forename: Anders Højgaard
authors.initials: AH
authors.lastname: Hansen
authors.forename: Kristian Tølbøl
authors.initials: KT
authors.lastname: Sørensen
authors.forename: Richard
authors.initials: R
authors.lastname: Mathieu
authors.forename: Alois
authors.initials: A
authors.lastname: Serer
authors.forename: Lars
authors.initials: L
authors.lastname: Duelund
authors.forename: Himanshu
authors.initials: H
authors.lastname: Khandelia
authors.forename: Per Lyngs
authors.initials: PL
authors.lastname: Hansen
authors.forename: Adam Cohen
authors.initials: AC
authors.lastname: Simonsen
mesh_terms: D015060:1,2-Dipalmitoylphosphatidylcholine / Q000737:chemistry / Q000378:metabolism*; D018686:Anesthetics, Intravenous / Q000032:analysis / Q000494:pharmacology*; D000818:Animals; D002152:Calorimetry, Differential Scanning; D008051:Lipid Bilayers / Q000737:chemistry / Q000378:metabolism*; D051379:Mice; D056004:Molecular Dynamics Simulation; D044367:Phase Transition / Q000187:drug effects*; D015742:Propofol / Q000032:analysis / Q000494:pharmacology*
chemical_list: D018686:Anesthetics, Intravenous; D008051:Lipid Bilayers; D015060:1,2-Dipalmitoylphosphatidylcholine; D015742:Propofol
keywords: Anesthesia; Calorimetry; Langmuir monolayer; Lipid bilayer; Molecular dynamics simulations; Propofol