title: How the spontaneous insertion of amphiphilic imidazolium-based cations changes biological membranes: a molecular simulation study.
abstract: The insertion of 1-octyl-3-methylimidazolium cations (OMIM(+)) from a diluted aqueous ionic liquid (IL) solution into a model of a bacterial cell membrane is investigated. Subsequently, the mutual interactions of cations inside the membrane and their combined effect on membrane properties are derived. The ionic liquid solution and the membrane model are simulated using molecular dynamics in combination with empirical force fields. A high propensity of OMIM(+) for membrane insertion is observed, with a cation concentration at equilibrium inside the membrane 47 times larger than in the solvent. Once inserted, cations exhibit a weak effective attraction inside the membrane at a distance of 1.3 nm. At this free energy minimum, negatively charged phosphates of the phospholipids are sandwiched between two OMIM(+) to form energetically favorable OMIM(+)-phosphate-OMIM(+) types of coordination. The cation-cation association free energy is 5.9 kJ mol(-1), whereas the activation barrier for dissociation is 10.1 kJ mol(-1). Subsequently, OMIM(+) are inserted into the leaflet of the membrane bilayer that represents the extracellular side. The cations are evenly distributed with mutual cation distances according to the found optimum distance of 1.3 nm. Because of the short length of the cation alkyl chains compared to lipid fatty acids, voids are generated in the hydrophobic core of the membrane. These voids disorder the fatty acids, because they enable fatty acids to curl into these empty spaces and also cause a thinning of the membrane by 0.6 nm. Additionally, the membrane density increases at its center. The presence of OMIM(+) in the membrane facilitates the permeation of small molecules such as ammonia through the membrane, which is chosen as a model case for small polar solutes. The permeability coefficient of the membrane with respect to ammonia increases substantially by a factor of seven. This increase is caused by a reduction of the involved free energy barriers, which is effected by the cations through the thinning of the membrane and favorable interactions of the delocalized OMIM(+) charge with ammonia inside the membrane. Overall, the results indicate the antimicrobial effect of amphiphilic imidazolium-based cations that are found in various common ILs. This effect is caused by an alteration of the permeability of the bacterial membrane and other property changes.
authors.affiliation: Institute of High Performance Computing, Agency for Science, Technology and Research, 1 Fusionopolis Way, #16-16, Connexis, Singapore 138632, Republic of Singapore.
authors.forename: Geraldine S
authors.initials: GS
authors.lastname: Lim
authors.affiliation: National University of Singapore, Department of Chemistry, 3 Science Drive 3, Singapore 117543, Republic of Singapore.
authors.forename: Stephan
authors.initials: S
authors.lastname: Jaenicke
authors.affiliation: Institute of Chemical and Engineering Sciences, Agency for Science, Technology and Research, 1 Pesek Road, Jurong Island, Singapore 627833, Republic of Singapore. klahnm@ices.a-star.edu.sg.
authors.forename: Marco
authors.initials: M
authors.lastname: Klähn
mesh_terms: D002412:Cations / Q000737:chemistry; D002462:Cell Membrane / Q000737:chemistry*; D004926:Escherichia coli / Q000378:metabolism; D057927:Hydrophobic and Hydrophilic Interactions; D007093:Imidazoles / Q000737:chemistry*; D052578:Ionic Liquids / Q000737:chemistry; D008051:Lipid Bilayers / Q000737:chemistry; D056004:Molecular Dynamics Simulation; D013816:Thermodynamics
chemical_list: C528768:1-octyl-3-methylimidazolium; D002412:Cations; D007093:Imidazoles; D052578:Ionic Liquids; D008051:Lipid Bilayers