Simulating 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. Especially 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 nanoscale, 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 [4,5,9,12,13]. The remarkable properties of binary lipid/cholesterol mixtures have also been addressed [6,7].

More recently, focus has shifted to simulate the role of lipid flipflop in domain registration [15], and to probe the effect of other components on the stability of the phases [10,11,14]. We also succeeded to speed up the phase separation process in atomistic force field using a dual resolution approach, coupling Gromos and Martini [16].

  • [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.
  • [3] N. Kucerka, D. Marquardt, T.A. Harroun, M.P. Nieh, S.R. Wassall, D.H. de Jong, L.V. Schäfer, 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.
  • [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.
  • [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.
  • [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.
  • [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] G. Moiset, C.A. López, R. Bartelds, L. Syga, E. Rijpkema, A. Cukkemane, M. Baldus, B. Poolman, S.J. Marrink. Disaccharides impact the lateral organization of lipid membranes. JACS, 136:16167-16175, 2014. open access
  • [11] J. Barnoud, G. Rossi, S.J. Marrink, L. Monticelli. Hydrophobic compounds reshape membrane domains. PLoS Comp. Biol., 10: e1003873, 2014. open access
  • [12] J. Su, S.J. Marrink, M.N. Melo. Localization Preference of Antimicrobial Peptides on Liquid-Disordered Membrane Domains. Front. Cell Dev. Biol., 8:350, 2020.
  • [13] F. Sun, C.F.E. Schroer, C.R. Palacios, L. Xu, S.Z. Luo, S.J. Marrink. Molecular mechanism for bidirectional regulation of CD44 for lipid raft affiliation by palmitoylations and PIP2. PLoS Comput. Biol. 16:e1007777, 2020.
  • [14] Y. Liu, J. Barnoud, S.J. Marrink. Gangliosides Destabilize Lipid Phase Separation in Multicomponent Membranes. Biophys. J. 117: 1215-1223, 2019.
  • [15] S. Thallmair, H.I. Ingólfsson, S.J. Marrink. Cholesterol Flip-Flop Impacts Domain Registration in Plasma Membrane Models. J. Phys. Chem. Lett. 9:5527–5533, 2018. doi:10.1021/acs.jpclett.8b01877
  • [16] Y. Liu, A.H. de Vries, W. Pezeshkian, S.J. Marrink. Capturing Membrane Phase Separation by Dual Resolution Molecular Dynamics Simulations. J. Chem. Theory Comput. 2021, online.