title: Partitioning of caffeine in lipid bilayers reduces membrane fluidity and increases membrane thickness.
abstract: Caffeine is a small amphiphilic molecule, which is widely consumed as a stimulant to prevent fatigue, but is also used as a common drug adjuvant in modern medicine. Here, we show that caffeine interacts with unsaturated lipid membranes made of 1-palmitoyl-2-oleoyl-sn-glycero-3-phosphocholine (POPC). By combining X-ray diffraction and molecular dynamics simulations, we present evidence that caffeine partitions in lipid membranes and locates at the head group-tail group interface of the bilayers. By attracting water molecules from neighboring lipid molecules, it leads to the formation of "water pockets", i.e., a local increase of water density at this interface. Through this mechanism, caffeine leads to an overall decrease of the gauche defect density in the membranes and an increase of membrane thickness, indicating a loss of membrane fluidity. These non-specific membrane interactions may increase the efficacy of analgesic drugs through changes in the bioavailability and rate of metabolism of these drugs.
authors.affiliation: Department of Physics and Astronomy, McMaster University, ABB-241, 1280 Main Street West, Hamilton, Ontario L8S 4M1, Canada. rheinstadter@mcmaster.ca.
authors.forename: Adree
authors.initials: A
authors.lastname: Khondker
authors.affiliation: Department of Physics and Astronomy, McMaster University, ABB-241, 1280 Main Street West, Hamilton, Ontario L8S 4M1, Canada. rheinstadter@mcmaster.ca.
authors.forename: Alexander
authors.initials: A
authors.lastname: Dhaliwal
authors.affiliation: Department of Physics and Astronomy, McMaster University, ABB-241, 1280 Main Street West, Hamilton, Ontario L8S 4M1, Canada. rheinstadter@mcmaster.ca.
authors.forename: Richard J
authors.initials: RJ
authors.lastname: Alsop
authors.affiliation: Department of Physics and Astronomy, McMaster University, ABB-241, 1280 Main Street West, Hamilton, Ontario L8S 4M1, Canada. rheinstadter@mcmaster.ca.
authors.forename: Jennifer
authors.initials: J
authors.lastname: Tang
authors.affiliation: Department of Physics and Astronomy, McMaster University, ABB-241, 1280 Main Street West, Hamilton, Ontario L8S 4M1, Canada. rheinstadter@mcmaster.ca and Department of Applied Physics, Aalto University, Helsinki, Finland.
authors.forename: Matilda
authors.initials: M
authors.lastname: Backholm
authors.affiliation: Department of Physics and Astronomy, McMaster University, ABB-241, 1280 Main Street West, Hamilton, Ontario L8S 4M1, Canada. rheinstadter@mcmaster.ca.
authors.forename: An-Chang
authors.identifier: http://orcid.org/0000-0003-1379-7162
authors.initials: AC
authors.lastname: Shi
authors.affiliation: Department of Physics and Astronomy, McMaster University, ABB-241, 1280 Main Street West, Hamilton, Ontario L8S 4M1, Canada. rheinstadter@mcmaster.ca.
authors.forename: Maikel C
authors.identifier: http://orcid.org/0000-0002-0558-7475
authors.initials: MC
authors.lastname: Rheinstädter
mesh_terms: D002110:Caffeine / Q000737:chemistry*; D008051:Lipid Bilayers / Q000737:chemistry*; D008560:Membrane Fluidity / Q000502:physiology*; D056004:Molecular Dynamics Simulation; D010713:Phosphatidylcholines / Q000737:chemistry; D014961:X-Ray Diffraction
chemical_list: D008051:Lipid Bilayers; D010713:Phosphatidylcholines; D002110:Caffeine; C028694:1-palmitoyl-2-oleoylphosphatidylcholine