Lipid organization of the plasma membrane.

The detailed organization of cellular membranes remains rather elusive. Based on large-scale molecular dynamics simulations, we provide a high-resolution view of the lipid organization of a plasma membrane at an unprecedented level of complexity. Our plasma membrane model consists of 63 different lipid species, combining 14 types of headgroups and 11 types of tails asymmetrically distributed across the two leaflets, closely mimicking an idealized mammalian plasma membrane. We observe an enrichment of cholesterol in the outer leaflet and a general non-ideal lateral mixing of the different lipid species. Transient domains with liquid-ordered character form and disappear on the microsecond time scale. These domains are coupled across the two membrane leaflets. In the outer leaflet, distinct nanodomains consisting of gangliosides are observed. Phosphoinositides show preferential clustering in the inner leaflet. Our data provide a key view on the lateral organization of lipids in one of life's fundamental structures, the cell membrane.

[1]  J. Slotte,et al.  How the molecular features of glycosphingolipids affect domain formation in fluid membranes. , 2009, Biochimica et biophysica acta.

[2]  S. Hell,et al.  Direct observation of the nanoscale dynamics of membrane lipids in a living cell , 2009, Nature.

[3]  Siewert J. Marrink,et al.  The molecular face of lipid rafts in model membranes , 2008, Proceedings of the National Academy of Sciences.

[4]  Xianlin Han,et al.  Lipid rafts are enriched in arachidonic acid and plasmenylethanolamine and their composition is independent of caveolin-1 expression: a quantitative electrospray ionization/mass spectrometric analysis. , 2002, Biochemistry.

[5]  Siewert J Marrink,et al.  Transmembrane helices can induce domain formation in crowded model membranes. , 2012, Biochimica et biophysica acta.

[6]  M. Zuckermann,et al.  What's so special about cholesterol? , 2004, Lipids.

[7]  Marcus D. Collins,et al.  Tuning lipid mixtures to induce or suppress domain formation across leaflets of unsupported asymmetric bilayers , 2008, Proceedings of the National Academy of Sciences.

[8]  G. Meer,et al.  Membrane lipids: where they are and how they behave , 2008, Nature Reviews Molecular Cell Biology.

[9]  Anant K. Menon,et al.  Lipid landscapes and pipelines in membrane homeostasis , 2014, Nature.

[10]  R. Pagano,et al.  Measurement of spontaneous transfer and transbilayer movement of BODIPY-labeled lipids in lipid vesicles. , 1997, Biochemistry.

[11]  C. Robinson,et al.  Membrane proteins bind lipids selectively to modulate their structure and function , 2014, Nature.

[12]  M. Parrinello,et al.  Polymorphic transitions in single crystals: A new molecular dynamics method , 1981 .

[13]  Watt W. Webb,et al.  Imaging coexisting fluid domains in biomembrane models coupling curvature and line tension , 2003, Nature.

[14]  R. Larson,et al.  The MARTINI Coarse-Grained Force Field: Extension to Proteins. , 2008, Journal of chemical theory and computation.

[15]  M. A. Surma,et al.  Organellar lipidomics--background and perspectives. , 2013, Current opinion in cell biology.

[16]  D. Tieleman,et al.  Perspective on the Martini model. , 2013, Chemical Society reviews.

[17]  F. Maxfield,et al.  Sterols are mainly in the cytoplasmic leaflet of the plasma membrane and the endocytic recycling compartment in CHO cells. , 2008, Molecular biology of the cell.

[18]  M. Parrinello,et al.  Canonical sampling through velocity rescaling. , 2007, The Journal of chemical physics.

[19]  L. Bagatolli,et al.  Low PIP(2) molar fractions induce nanometer size clustering in giant unilamellar vesicles. , 2014, Chemistry and physics of lipids.

[20]  N. Loberto,et al.  Glycosphingolipid behaviour in complex membranes. , 2009, Biochimica et biophysica acta.

[21]  A. Shevchenko,et al.  Quantitative analysis of the lipidomes of the influenza virus envelope and MDCK cell apical membrane , 2012, The Journal of cell biology.

[22]  D. Engelman Membranes are more mosaic than fluid , 2005, Nature.

[23]  J. Dodge,et al.  Composition of Phospholipids and of Phospholipid Fatty Acids and Aldehydes in Human Red Cells , 1967 .

[24]  Xianlin Han,et al.  Electrospray ionization mass spectroscopic analysis of human erythrocyte plasma membrane phospholipids. , 1994, Proceedings of the National Academy of Sciences of the United States of America.

[25]  Carsten Kutzner,et al.  GROMACS 4:  Algorithms for Highly Efficient, Load-Balanced, and Scalable Molecular Simulation. , 2008, Journal of chemical theory and computation.

[26]  P. Somerharju,et al.  Phospholipid composition of the mammalian red cell membrane can be rationalized by a superlattice model. , 1998, Proceedings of the National Academy of Sciences of the United States of America.

[27]  J. P. Grossman,et al.  Biomolecular simulation: a computational microscope for molecular biology. , 2012, Annual review of biophysics.

[28]  Jeffery B. Klauda,et al.  CHARMM-GUI Membrane Builder for mixed bilayers and its application to yeast membranes. , 2009, Biophysical journal.

[29]  Klaus Schulten,et al.  Discovery through the computational microscope. , 2009, Structure.

[30]  Kai Simons,et al.  Lipid Rafts As a Membrane-Organizing Principle , 2010, Science.

[31]  S. Marrink,et al.  Molecular view on protein sorting into liquid-ordered membrane domains mediated by gangliosides and lipid anchors. , 2013, Faraday discussions.

[32]  D. Tieleman,et al.  The MARTINI force field: coarse grained model for biomolecular simulations. , 2007, The journal of physical chemistry. B.

[33]  A. Mark,et al.  Coarse grained model for semiquantitative lipid simulations , 2004 .

[34]  Siewert J Marrink,et al.  Lipids on the move: simulations of membrane pores, domains, stalks and curves. , 2009, Biochimica et biophysica acta.

[35]  Kai Simons,et al.  Membrane lipidome of an epithelial cell line , 2011, Proceedings of the National Academy of Sciences.

[36]  Prabuddha Sengupta,et al.  Critical fluctuations in plasma membrane vesicles. , 2008, ACS chemical biology.

[37]  L. Tamm,et al.  Transbilayer effects of raft-like lipid domains in asymmetric planar bilayers measured by single molecule tracking. , 2006, Biophysical journal.

[38]  D. Lingwood,et al.  Order of lipid phases in model and plasma membranes , 2009, Proceedings of the National Academy of Sciences.

[39]  Watt W. Webb,et al.  Large-scale fluid/fluid phase separation of proteins and lipids in giant plasma membrane vesicles , 2007, Proceedings of the National Academy of Sciences.

[40]  Siewert J Marrink,et al.  Simulation of gel phase formation and melting in lipid bilayers using a coarse grained model. , 2005, Chemistry and physics of lipids.

[41]  W F Drew Bennett,et al.  Molecular view of cholesterol flip-flop and chemical potential in different membrane environments. , 2009, Journal of the American Chemical Society.

[42]  P. Devaux,et al.  Transmembrane Asymmetry and Lateral Domains in Biological Membranes , 2004, Traffic.

[43]  Wonpil Im,et al.  E. coli outer membrane and interactions with OmpLA. , 2014, Biophysical journal.

[44]  M. Berkowitz,et al.  Molecular model of a cell plasma membrane with an asymmetric multicomponent composition: water permeation and ion effects. , 2009, Biophysical journal.

[45]  F W McLafferty,et al.  Quantitative analysis of phospholipids in functionally important membrane domains from RBL-2H3 mast cells using tandem high-resolution mass spectrometry. , 1999, Biochemistry.