title: Atomistic models of general anesthetics for use in in silico biological studies.
abstract: While small molecules have been used to induce anesthesia in a clinical setting for well over a century, a detailed understanding of the molecular mechanism remains elusive. In this study, we utilize ab initio calculations to develop a novel set of CHARMM-compatible parameters for the ubiquitous modern anesthetics desflurane, isoflurane, sevoflurane, and propofol for use in molecular dynamics (MD) simulations. The parameters generated were rigorously tested against known experimental physicochemical properties including dipole moment, density, enthalpy of vaporization, and free energy of solvation. In all cases, the anesthetic parameters were able to reproduce experimental measurements, signifying the robustness and accuracy of the atomistic models developed. The models were then used to study the interaction of anesthetics with the membrane. Calculation of the potential of mean force for inserting the molecules into a POPC bilayer revealed a distinct energetic minimum of 4-5 kcal/mol relative to aqueous solution at the level of the glycerol backbone in the membrane. The location of this minimum within the membrane suggests that anesthetics partition to the membrane prior to binding their ion channel targets, giving context to the Meyer-Overton correlation. Moreover, MD simulations of these drugs in the membrane give rise to computed membrane structural parameters, including atomic distribution, deuterium order parameters, dipole potential, and lateral stress profile, that indicate partitioning of anesthetics into the membrane at the concentration range studied here, which does not appear to perturb the structural integrity of the lipid bilayer. These results signify that an indirect, membrane-mediated mechanism of channel modulation is unlikely.
authors.affiliation: Center for Biophysics and Computational Biology, Department of Biochemistry, College of Medicine, and Beckman Institute for Advanced Science and Technology, University of Illinois at Urbana-Champaign , Urbana, Illinois 61801, United States.
authors.forename: Mark J
authors.initials: MJ
authors.lastname: Arcario
authors.forename: Christopher G
authors.initials: CG
authors.lastname: Mayne
authors.forename: Emad
authors.initials: E
authors.lastname: Tajkhorshid
mesh_terms: D018681:Anesthetics, General / Q000737:chemistry* / Q000378:metabolism* / Q000494:pharmacology; D002462:Cell Membrane / Q000737:chemistry / Q000378:metabolism; D003198:Computer Simulation; D007473:Ion Channels / Q000378:metabolism; D008051:Lipid Bilayers / Q000737:chemistry / Q000378:metabolism; D008968:Molecular Conformation; D056004:Molecular Dynamics Simulation; D010713:Phosphatidylcholines / Q000737:chemistry / Q000378:metabolism; D015203:Reproducibility of Results
chemical_list: D018681:Anesthetics, General; D007473:Ion Channels; D008051:Lipid Bilayers; D010713:Phosphatidylcholines; C028694:1-palmitoyl-2-oleoylphosphatidylcholine