Lipid rafts

Cell membranes contain a large number of different lipid species. Such a multicomponent mixture exhibits a complex phase behavior with regions of structural and compositional heterogeneity. Domains formed in ternary mixtures composed of saturated and unsaturated lipids together with cholesterol have received a lot of attention as they may resemble raft formation in real cells.

We are using MARTINI to assess the molecular nature of these domains at the nano- and mesoscales, information that has thus far eluded experimental determination. We are able to simulate the spontaneous separation of a saturated phosphatidylcholine (PC)/unsaturated PC/cholesterol mixture into a liquid-ordered and a liquid-disordered phase with structural and dynamic properties closely matching experimental data. The near-atomic resolution of the simulations reveals remarkable features of both domains and the boundary domain interface [1-3,8], as well as on the sorting and clustering of model transmembrane proteins in such a domain segregated membrane [4,5,9]. In addition, the properties of binary lipid/cholesterol mixtures have also been addressed [6,7].

The size- and timescales of simulations of raft formation recently got boosted by the introduction of the implicit-solvent Martini model, or Dry Martini [10]. Domain segregation is observed in Dry Martini under the same conditions as it occurs for the regular model, at a severalfold speedup in performance.

[1] H.J. Risselada, S.J. Marrink. The molecular face of lipid rafts in model membranes. PNAS, 105:17367-17372, 2008. open access
[2] T. Apajalahti, P. Niemela, P.N. Govindan, M. Miettinen, E. Salonen, S.J. Marrink, I. Vattulainen. Concerted diffusion of lipids in raft-like membranes. Farad. Discuss., 144:411-430, 2010. abstract
[3] N. Kucerka, D. Marquardt, T.A. Harroun, M.P. Nieh, S.R. Wassall, D.H. de Jong, L.V. Schaefer, S.J. Marrink, J. Katsaras. Cholesterol in bilayers with PUFA chains: Doping with DMPC or POPC results in sterol reorientation and membrane-domain formation. Biochemistry, 49:7485-7493, 2010. abstract
[4] L.V. Schafer, D.H. de Jong, A. Holt, A.J. Rzepiela, A.H. de Vries, B. Poolman, J.A. Killian, S.J. Marrink. Lipid packing drives the segregation of transmembrane helices into disordered lipid domains in model biomembranes. PNAS, 108:1343-1348, 2011. open access
[5] J. Domanski, S.J. Marrink, L.V. Schaefer. Transmembrane helices can induce domain formation in crowded model biomembranes. BBA Biomembr., 1818:984-994, 2012. abstract
[6] W.F.D. Bennett, J.L. MacCallum, M.J. Hinner, S.J. Marrink, D.P. Tieleman. A molecular view of cholesterol flip-flop and chemical potential in different membrane environments. JACS, 131:12714-12720, 2009. abstract
[7] S.J. Marrink, A.H. de Vries, T.A. Harroun, J. Katsaras, S.R. Wassall. Cholesterol shows preference for the interior of polyunsaturated lipid membranes. JACS, 130:10-11, 2008. abstract
[8] H.J. Risselada, S.J. Marrink, M. Muller. Curvature-dependent elastic properties of liquid-ordered domains result in inverted domain sorting on uniaxially compressed vesicles. Phys. Rev. Lett., 106:148102, 2011. abstract
[9] D.H. de Jong, C.A. Lopez, S.J. Marrink. Molecular view on protein sorting into liquid-ordered membrane domains mediated by gangliosides and lipid anchors. Farad. Discuss., 161:347-363, 2013. abstract
[10] C. Arnarez, J.J. Uusitalo, M.F. Masman, H.I. Ingolfsson, D.H. de Jong, M.N. Melo, X. Periole, A.H. de Vries, S.J. Marrink. Dry Martini: coarse grained implicit water force field for (bio)molecular simulations. J. Chem. Theory Comput., 11:260-275, 2015. abstract