title: The Role of Atomic Polarization in the Thermodynamics of Chloroform Partitioning to Lipid Bilayers.
abstract: In spite of extensive research and use in medical practice, the precise molecular mechanism of volatile anesthetic action remains unknown. The distribution of anesthetics within lipid bilayers and potential targeting to membrane proteins is thought to be central to therapeutic function. Therefore, obtaining a molecular level understanding of volatile anesthetic partitioning into lipid bilayers is of vital importance to modern pharmacology. In this study we investigate the partitioning of the prototypical anesthetic, chloroform, into lipid bilayers and different organic solvents using molecular dynamics simulations with potential models ranging from simplified coarse-grained MARTINI to additive and polarizable CHARMM all-atom force fields. Many volatile anesthetics display significant inducible dipole moments, which correlate with their potency, yet the exact role of molecular polarizability in their stabilization within lipid bilayers remains unknown. We observe that explicit treatment of atomic polarizability makes it possible to accurately reproduce solvation free energies in solvents with different polarities, allowing for quantitative studies in heterogeneous molecular distributions, such as lipid bilayers. We calculate the free energy profiles for chloroform crossing lipid bilayers to reveal a role of polarizability in modulating chloroform partitioning thermodynamics via the chloroform-induced dipole moment and highlight competitive binding to the membrane core and toward the glycerol backbone that may have significant implications for understanding anesthetic action.
authors.affiliation: Department of Chemistry, University of California , Davis, One Shields Avenue, Davis, California 95616, United States.
authors.forename: Igor
authors.initials: I
authors.lastname: Vorobyov
authors.affiliation: Department of Biological Sciences, University of Calgary , 2500 University Drive, Calgary, Canada, T2N 2N4.
authors.forename: W F Drew
authors.initials: WF
authors.lastname: Bennett
authors.affiliation: Department of Biological Sciences, University of Calgary , 2500 University Drive, Calgary, Canada, T2N 2N4.
authors.forename: D Peter
authors.initials: DP
authors.lastname: Tieleman
authors.affiliation: Department of Chemistry, University of California , Davis, One Shields Avenue, Davis, California 95616, United States.
authors.forename: Toby W
authors.initials: TW
authors.lastname: Allen
authors.affiliation: Department of Biological Sciences, University of Calgary , 2500 University Drive, Calgary, Canada, T2N 2N4.
authors.forename: Sergei
authors.initials: S
authors.lastname: Noskov