title: Interdigitation of long-chain sphingomyelin induces coupling of membrane leaflets in a cholesterol dependent manner.
abstract: It has been a long-standing question how the two leaflets in a lipid bilayer modulate each others' physical properties. In this paper, we discuss how this interaction may take place through interdigitation. We use atomistic molecular dynamics simulations to consider asymmetric lipid membrane models whose compositions are based on the lipidomics data determined for exosomes released by PC-3 prostate cancer cells. The simulations show interdigitation to be exceptionally strong for long-chain sphingomyelin (SM) molecules. In asymmetric membranes the amide-linked chain of SM is observed to extend deep into the opposing membrane leaflet. Interestingly, we find that the conformational order of the amide-linked SM chain increases the deeper it penetrates to the opposing leaflet. Analysis of this finding reveals that the amide-linked SM chain interacts favorably with the lipid chains in the opposite leaflet, and that cholesterol modulates the effect of SM interdigitation by influencing the conformational order of lipid hydrocarbon chains in the opposing (cytosolic) leaflet.
authors.affiliation: Department of Physics, Tampere University of Technology, P. O. Box 692, FI-33101 Tampere, Finland.
authors.forename: Tomasz
authors.initials: T
authors.lastname: Róg
authors.affiliation: Department of Physics, Tampere University of Technology, P. O. Box 692, FI-33101 Tampere, Finland; Department of Physics and Energy, University of Limerick, Limerick, Ireland.
authors.forename: Adam
authors.initials: A
authors.lastname: Orłowski
authors.affiliation: Department of Molecular Cell Biology, Institute for Cancer Research, Oslo University Hospital, The Norwegian Radium Hospital, 0316 Oslo, Norway; Centre for Cancer Biomedicine, Faculty of Medicine, University of Oslo, 0316 Oslo, Norway.
authors.forename: Alicia
authors.initials: A
authors.lastname: Llorente
authors.affiliation: Department of Molecular Cell Biology, Institute for Cancer Research, Oslo University Hospital, The Norwegian Radium Hospital, 0316 Oslo, Norway; Centre for Cancer Biomedicine, Faculty of Medicine, University of Oslo, 0316 Oslo, Norway.
authors.forename: Tore
authors.initials: T
authors.lastname: Skotland
authors.affiliation: Zora Biosciences Oy, 02150 Espoo, Finland.
authors.forename: Tuulia
authors.initials: T
authors.lastname: Sylvänne
authors.affiliation: Zora Biosciences Oy, 02150 Espoo, Finland.
authors.forename: Dimple
authors.initials: D
authors.lastname: Kauhanen
authors.affiliation: Zora Biosciences Oy, 02150 Espoo, Finland.
authors.forename: Kim
authors.initials: K
authors.lastname: Ekroos
authors.affiliation: Department of Molecular Cell Biology, Institute for Cancer Research, Oslo University Hospital, The Norwegian Radium Hospital, 0316 Oslo, Norway; Centre for Cancer Biomedicine, Faculty of Medicine, University of Oslo, 0316 Oslo, Norway; Department of Biosciences, University of Oslo, 0316 Oslo, Norway.
authors.forename: Kirsten
authors.initials: K
authors.lastname: Sandvig
authors.affiliation: Department of Physics, Tampere University of Technology, P. O. Box 692, FI-33101 Tampere, Finland; MEMPHYS - Center for Biomembrane Physics, University of Southern Denmark, Odense, Denmark; Department of Physics, University of Helsinki, P.O. Box 43, FI-00014 Helsinki, Finland. Electronic address: Ilpo.Vattulainen@tut.fi.
authors.forename: Ilpo
authors.initials: I
authors.lastname: Vattulainen
mesh_terms: D045744:Cell Line, Tumor; D002462:Cell Membrane / Q000378:metabolism*; D002784:Cholesterol / Q000378:metabolism*; D006801:Humans; D008297:Male; D008954:Models, Biological; D011471:Prostatic Neoplasms / Q000378:metabolism*; D013109:Sphingomyelins / Q000378:metabolism*
chemical_list: D013109:Sphingomyelins; D002784:Cholesterol
keywords: Cholesterol; Computer simulation; Exosome; Interdigitation; Lipid membrane; Lipidomics; Molecular dynamics simulation; Sphingomyelin