Collaborators: J. A. Killian (Utrecht University, NL), B. Poolman (University of Groningen, NL); N. Kucerka and J. Katsaras (Oak Ridge National Lab, Canada)
Supported by: Netherlands Organisation for Scientific Research (NWO)
Cell membranes are heterogeneously structured materials comprised of (mainly) lipids and proteins. They can be crowded with proteins, and they can be "patchy": Distinct membrane regions can be enriched in certain types of lipids and proteins, whereas other molecules can accumulate in different regions. These patches, which have been termed 'rafts' in real cell membranes, can play various physiologial roles, for example in cellular trafficking, signaling, and the sorting, folding, and self-assembly of membrane proteins into functional clusters. How exactly model membranes, in which macroscopic phase-separation into so-called liquid-disordered and liquid-ordered lipid domains can occur, and 'rafts' in real cell membranes are connected is not fully understood. In any case, experimentally, it is very challenging to investigate the organization of biological membranes. This is mainly due to the lack of methods that have the required spatial and temporal resolution required to study the interactions in fluctuating ensembles of lipids and proteins on the level of the individual molecules.
Molecular dynamics (MD) simulations are a formidable tool to study protein-lipid and protein-protein interactions in biological model membranes. In particular, we wanted to answer the following questions:
To address these questions, we combined MD simulations and fluorescence microscopy (see Figure). The simulations yielded a detailed understanding of the free energy differences that drive the lateral mixing behavior of lipids and transmembrane helices domains, including enthalpic and entropic contributions. Using our recent reverse mapping algorithm to transform coarse-grained to their corresponding atomistic structures, we combined computationally efficient coarse-grained with accurate atomistic resolution models in a hierarchical modelling approach (sequential multiscaling).
J. Domanski, S. J. Marrink. L. V. Schäfer: Transmembrane Helices can Induce Domain Formation in Crowded Model Membranes, BBA - Biomembranes, 2012, 1818, 984-994. (doi)
L. V. Schäfer, 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 Membranes, Proc. Nat. Acad. Sci. USA, 2011, 108 (4), 1343-1348. (doi).
L. V. Schäfer, S. J. Marrink: Partitioning of Lipids at Domain Boundaries in Model Membranes, Biophys. J., 2010, 99 (12), L91-L93. (doi)
A. J. Rzepiela, L. V. Schäfer, N. Goga, H. J. Risselada, A. H. de Vries, S. J. Marrink: Reconstruction of atomistic details from coarse-grained structures, J. Comput. Chem., 2010, 31 (6), 1333-1343. (doi)
S. Ramadurai, A. Holt, L. V. Schäfer, V. V. Krasnikov, D.T.S. Rijkers, S. J. Marrink, J. A. Killian, B. Poolman: Influence of Hydrophobic Mismatch and Amino Acid Composition on the Lateral Diffusion of Transmembrane Peptides, Biophys. J., 2010, 99 (5), 1447-1454. (doi)
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, 2010, 49 (35), 7485-7493. (doi)