Molecular simulation of rapid translocation of cholesterol, diacylglycerol, and ceramide in model raft and nonraft membranes

The translocation of lipids across membranes (flip-flop) is an important biological process. Slow exchange on a physiological timescale allows the creation of asymmetric distributions of lipids across cellular membranes. The location of lipids and their rate of exchange have important biological consequences, especially for lipids involved in cellular signaling. We investigated the translocation of cholesterol, ceramide, and diacylglycerol in two model bilayers using molecular dynamics simulations. We estimate half times for flip-flop for cholesterol, diacylglycerol, and ceramide of 20 μs, 30 μs, and 10 ms in a POPC bilayer, compared with approximately 30 min, 30 ms, and 30 s in a model raft bilayer (1:1:1 PSM, POPC, and cholesterol). Cholesterol has a large (54 kJ/mol) free energy of exchange between the POPC and raft bilayer, and therefore, it strongly prefers the more ordered and rigid raft bilayer over the more liquid POPC bilayer. Ceramide and diacylglycerol have relatively small free energies of exchange, suggesting nearly equal preference for both bilayers. This unexpected result may have implications for ceramide and diacylglycerol signaling and membrane localization. The translocation of lipids across membranes (flip-flop) is an important biological process. Slow exchange on a physiological timescale allows the creation of asymmetric distributions of lipids across cellular membranes. The location of lipids and their rate of exchange have important biological consequences, especially for lipids involved in cellular signaling. We investigated the translocation of cholesterol, ceramide, and diacylglycerol in two model bilayers using molecular dynamics simulations. We estimate half times for flip-flop for cholesterol, diacylglycerol, and ceramide of 20 μs, 30 μs, and 10 ms in a POPC bilayer, compared with approximately 30 min, 30 ms, and 30 s in a model raft bilayer (1:1:1 PSM, POPC, and cholesterol). Cholesterol has a large (54 kJ/mol) free energy of exchange between the POPC and raft bilayer, and therefore, it strongly prefers the more ordered and rigid raft bilayer over the more liquid POPC bilayer. Ceramide and diacylglycerol have relatively small free energies of exchange, suggesting nearly equal preference for both bilayers. This unexpected result may have implications for ceramide and diacylglycerol signaling and membrane localization. The lipid raft hypothesis states that mammalian cellular membranes contain lateral domains enriched in cholesterol, sphingomyelin, and specific integral membrane proteins (1Pike L.J. Rafts defined: a report on the Keystone Symposium on Lipid Rafts and Cell Function.J. Lipid Res. 2006; 47: 1597-1598Abstract Full Text Full Text PDF PubMed Scopus (1141) Google Scholar, 2Simons K. Ikonen E. Functional rafts in cell membranes.Nature. 1997; 387: 569-572Crossref PubMed Scopus (8157) Google Scholar, 3Simons K. Vaz W.L. Model systems, lipid rafts, and cell membranes.Annu. Rev. Biophys. Biomol. Struct. 2004; 33: 269-295Crossref PubMed Scopus (1366) Google Scholar–4Edidin M. The state of lipid rafts: from model membranes to cells.Annu. Rev. Biophys. Biomol. Struct. 2003; 32: 257-283Crossref PubMed Scopus (1138) Google Scholar). Rafts are thought be small (approximately tens of nanometers in diameter), dynamic, and important for cellular signaling and membrane trafficking (1Pike L.J. Rafts defined: a report on the Keystone Symposium on Lipid Rafts and Cell Function.J. Lipid Res. 2006; 47: 1597-1598Abstract Full Text Full Text PDF PubMed Scopus (1141) Google Scholar, 5Eggeling C. Ringemann C. Medda R. Schwarzmann G. Sandhoff K. Polyakova S. Belov V.N. Hein B. von Middendorff C. Schonle A. et al.Direct observation of the nanoscale dynamics of membrane lipids in a living cell.Nature. 2009; 457: 1159-1162Crossref PubMed Scopus (1198) Google Scholar). The sorting of lipids and proteins and the role of lipid rafts in vivo remains controversial (4Edidin M. The state of lipid rafts: from model membranes to cells.Annu. Rev. Biophys. Biomol. Struct. 2003; 32: 257-283Crossref PubMed Scopus (1138) Google Scholar, 6Munro S. Lipid rafts: elusive or illusive?.Cell. 2003; 115: 377-388Abstract Full Text Full Text PDF PubMed Scopus (1333) Google Scholar, 7Lingwood D. Simons K. Lipid rafts as a membrane-organizing principle.Science. 2010; 327: 46-50Crossref PubMed Scopus (3261) Google Scholar–8Hancock J.F. Lipid rafts: contentious only from simplistic standpoints.Nat. Rev. Mol. Cell Biol. 2006; 7: 456-462Crossref PubMed Scopus (672) Google Scholar). The microscopic structure of mixed membranes is a complex problem because the local concentration of individual lipids affects the phase and structure of the membrane, which in turn affect the local concentration of these lipids. In a model system, it has been shown that both C18:0 ceramide and dipalmitoylglycerol can displace cholesterol from liquid-ordered domains, and form larger and more stable domains than cholesterol-enriched ordered domains (9London Megha E. Ceramide selectively displaces cholesterol from ordered lipid domains (rafts): implications for lipid raft structure and function.J. Biol. Chem. 2004; 279: 9997-10004Abstract Full Text Full Text PDF PubMed Scopus (368) Google Scholar). Both ceramide (10López-Montero I. Monroy F. Vélez M. Devaux P.F. Ceramide: from lateral segregation to mechanical stress.Biochim. Biophys. Acta. 2010; 1798: 1348-1356Crossref PubMed Scopus (45) Google Scholar) and diacylglycerol (11Gómez-Fernández J.C. Corbalán-García S. Diacylglycerols, multivalent membrane modulators.Chem. Phys. Lipids. 2007; 148: 1-25Crossref PubMed Scopus (63) Google Scholar) are nonlamellar forming lipids, which are important for cellular processes, such as pore formation, vesicle fusion, and budding, as well as membrane protein function (12Epand R.M. Lipid polymorphism and protein-lipid interactions.Biochim. Biophys. Acta. 1998; 1376: 353-368Crossref PubMed Scopus (325) Google Scholar). Currently we lack a molecular level physical and thermodynamic understanding of lipid-lipid interactions in biological membranes. Ceramide is a key metabolic intermediate for sphingolipids with an amide backbone (13Hannun Y.A. Obeid L.M. Principles of bioactive lipid signalling: lessons from sphingolipids.Nat. Rev. Mol. Cell Biol. 2008; 9: 139-150Crossref PubMed Scopus (2484) Google Scholar), as diacylglycerol is for glycerol-derived phospholipids (14Carrasco S. Mérida I. Diacylglycerol, when simplicity becomes complex.Trends Biochem. Sci. 2007; 32: 27-36Abstract Full Text Full Text PDF PubMed Scopus (296) Google Scholar). In cells, there are many variants of both ceramide (13Hannun Y.A. Obeid L.M. Principles of bioactive lipid signalling: lessons from sphingolipids.Nat. Rev. Mol. Cell Biol. 2008; 9: 139-150Crossref PubMed Scopus (2484) Google Scholar) and diacylglycerol (15Goñi F.M. Alonso A. Structure and functional properties of diacylglycerols in membranes.Prog. Lipid Res. 1999; 38: 1-48Crossref PubMed Scopus (215) Google Scholar), including short and long tails, saturated and unsaturated tails, and minor changes in backbone structure. Both ceramide and diacylglycerol are lipid second messengers that play important roles in many signaling pathways. The mechanism of lipid second messengers can involve specific lipid-protein interactions or more general membrane altering effects, such as vesicle budding and domain formation or stabilization. A well-studied example of a specific lipid-protein mechanism is the breakdown of phosphoinositol or phosphatidylcholine by a phospholipase into diacylglycerol, which then binds to the C1 domain of protein kinase C (14Carrasco S. Mérida I. Diacylglycerol, when simplicity becomes complex.Trends Biochem. Sci. 2007; 32: 27-36Abstract Full Text Full Text PDF PubMed Scopus (296) Google Scholar). The formation of larger and more stable domains, or signaling platforms, with the creation of ceramide by sphingomyelinase, is an example of a nonspecific mechanism of signaling (13Hannun Y.A. Obeid L.M. Principles of bioactive lipid signalling: lessons from sphingolipids.Nat. Rev. Mol. Cell Biol. 2008; 9: 139-150Crossref PubMed Scopus (2484) Google Scholar). The localization and dynamics of signaling lipids is crucial to their function, particularly with respect to the distribution across the bilayer leaflets, as lipids on one leaflet are effectively isolated from the other side. Ceramide created by neutral sphingomyelinase on the cytoplasmic leaflet is involved with a different signaling pathway than is ceramide generated on the outer leaflet by acid sphingomyelinase (13Hannun Y.A. Obeid L.M. Principles of bioactive lipid signalling: lessons from sphingolipids.Nat. Rev. Mol. Cell Biol. 2008; 9: 139-150Crossref PubMed Scopus (2484) Google Scholar). The translocation of lipids from one bilayer leaflet to another, or flip-flop, is an important process for cellular growth, lipid transport, and signaling. It has been well established that the passive translocation of lipids with charged or zwitterionic headgroups is slow on a physiological timescale, with an estimated half time of hours to days (16Kornberg R.D. McConnell H.M. Inside-outside transitions of phospholipids in vesicle membranes.Biochemistry. 1971; 10: 1111-1120Crossref PubMed Scopus (780) Google Scholar, 17De Kruijff B. Van Zoelen E.J. Effect of the phase transition on the transbilayer movement of dimyristoyl phosphatidylcholine in Biophys. Acta. PubMed Scopus Google Cholesterol from small and large Biophys. Acta. PubMed Scopus Google Scholar). that lipid including and have been and functional of integral membrane proteins is of in the 2008; PubMed Scopus Google Scholar). The headgroups of cholesterol, diacylglycerol, and ceramide these lipids can bilayers on a timescale than hypothesis flip-flop of cholesterol and in implications for membrane 2003; PubMed Scopus Google Scholar, The and transbilayer movement of diacylglycerols in Biol. Chem. Full Text PDF PubMed Google Scholar, D. transbilayer of and to of membrane PubMed Scopus Google Scholar, A. of implications for membrane 2009; Full Text Full Text PDF PubMed Scopus Google Scholar, A. I. F. F. Devaux P.F. of ceramide and in the liquid ordered Biol. 2009; PubMed Scopus Google Scholar, I. S. A. M. Devaux P.F. transbilayer movement of in and in Biol. Chem. Full Text Full Text PDF PubMed Scopus Google Scholar, cell membrane cholesterol movement with Full Text Full Text PDF PubMed Scopus Google R. of to transbilayer movement and lipid of Full Text Full Text PDF PubMed Scopus Google Scholar), the on the by of may be to with the of the complex it more that can be by a of in the structure and dynamics of the membranes on the and of lipid of lipid bilayers are on the of membrane domains, and Biophys. Acta. 2009; PubMed Scopus Google Scholar, molecular dynamics of model biological membranes Biophys. Acta. 2009; PubMed Scopus Google Scholar, I. molecular interactions in lipid raft Biophys. Acta. 2009; PubMed Scopus Google of model Biophys. Acta. 2009; PubMed Scopus Google Scholar). we investigated cholesterol flip-flop and using molecular dynamics in phosphatidylcholine lipid bilayers of cholesterol flip-flop and in different membrane Chem. 2009; PubMed Scopus Google Scholar). We that cholesterol across with a large in between a bilayer, a bilayer, and a bilayer with A different using the and of free energy to for cholesterol in and bilayers S. Cholesterol from free energy Phys. Chem. B. 2010; PubMed Scopus Google Scholar). We that cholesterol in bilayers the free energy for flip-flop and pore formation of the of cholesterol on lipid Chem. 2009; PubMed Scopus Google Scholar). we that saturated lipids with short flip-flop of than lipids a mechanism of flip-flop and for a of phosphatidylcholine 2009; Scopus Google Scholar). we have to the of cholesterol, and with an ordered and rigid bilayer of POPC, and and with a POPC bilayer. We free energy for a lipid from the phase to the of the two different bilayers. the we estimated of flip-flop for cholesterol, ceramide, and diacylglycerol in the raft bilayer to as compared with a POPC bilayer. Cholesterol has a large free energy of exchange between the POPC and ceramide and diacylglycerol have free energies of exchange or for both bilayers. We two model POPC and a of PSM, cholesterol, and POPC lipids as a model bilayer. for POPC F. dynamics of a bilayer of and 1997; Full Text PDF PubMed Scopus Google Scholar). for I. Structure and dynamics of to 2004; Full Text Full Text PDF PubMed Scopus Google Scholar) and cholesterol M. B. von dynamics of lipid and Biophys. Acta. PubMed Scopus Google Scholar) have been and from and POPC by the with a with from the The Scholar). we the model for in to protein B. D. The Google Scholar). with D. E. B. G. and Chem. PubMed Scopus Google Scholar). and using S. an of the and for rigid Chem. Scopus Google Scholar), and other using B. a for molecular Chem. 1997; Scopus Google Scholar). The time with 10 using the G. D. M. Chem. Phys. 2007; PubMed Scopus Google Scholar). and to the bilayer using the A. dynamics with to an Chem. Phys. 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Scopus Google Scholar). we two in one in with the lipid by We have shown that the for a lipid is by using one or two in the and pore formation in and lipid the of Chem. 7: PubMed Scopus Google Scholar). the model we to estimate the rate of flip-flop across a lipid bilayer, with the rate to from to the of the bilayer and the rate to from the bilayer to In a of cholesterol flip-flop and in different membrane Chem. 2009; PubMed Scopus Google Scholar), we that for the rate for cholesterol flip-flop from simulations. we a lipid into the of a bilayer and it there for with a We then the and the time for the lipid to the in the bilayer. We times for cholesterol, diacylglycerol, and ceramide in the POPC bilayers. the we the time to with the of the we for from to the long timescale to the free energy We of and We then the to to the and properties of and POPC estimated by the on the lipid the bilayer and the time it to to rate for lipid time for lipid estimated by the on the lipid the bilayer and the time it to to rate for lipid time for lipid in a the free energy between and the bilayer and the rate for the lipid to from the bilayer to we can estimate a rate for the is the rate to from the bilayer to is the free energy and is the rate to from to the bilayer We then the rate of flip-flop using the rate to the bilayer and the rate to from the bilayer to We the rate by one half to for lipids that the bilayer then to their the rate of flip-flop, we then estimate the half time for flip-flop of the POPC and bilayers are shown in the of cholesterol, ceramide, and diacylglycerol the The are shown in Both bilayers have the and in the of the bilayer. The bilayer has a more complex with to is a the of the POPC bilayer and a the of the bilayer, because the two ordered are to as as more bilayers. The POPC bilayer is and more than the bilayer. for the of diacylglycerol in bilayer. that the bilayer is more ordered than the POPC bilayer. for cholesterol, and from to the of POPC and bilayers. the a of a free energy the of the in the bilayer and free energy from to or the bilayer The free energy for to is than the free energy for The important free energy are in The in the across the of as a of the to lipid to the of the bilayer. lipids have larger in the POPC bilayer than in the bilayer. has larger than cholesterol or ceramide in both bilayers. Both model bilayers are and therefore, the free energy shown in are a flip-flop a lipid from to the of the bilayer and then to the other The in the between and the bilayer is the free energy for The free energy for cholesterol, diacylglycerol, and ceramide flip-flop in POPC are compared with the bilayer. cholesterol, the free energy for flip-flop from to for the POPC and bilayers. has for flip-flop of and for the POPC and bilayers. The free energy for ceramide flip-flop in the POPC and bilayers from to the of between the cholesterol, diacylglycerol, or ceramide and the of the bilayer as the lipid from to the of the bilayer. the is into the bilayer of into the to with the is an between the lipid and the bilayer We have in the of charged and acid in a bilayer of in a lipid bilayer from 2008; Full Text Full Text PDF PubMed Scopus Google Scholar). ceramide from to from the POPC bilayer to with the by the of to The for the bilayer have compared with the POPC bilayer. The and structure it more to the lipid into the free energy between and the lipid are diacylglycerol and ceramide form one the of the bilayer, the of for ceramide and cholesterol are to an the of the bilayer to with the This is to the in the of the bilayer and to the small free energy the of the bilayer for cholesterol and ceramide ceramide with a the of the of ceramide and cholesterol in model membranes. The is the as in the ceramide or cholesterol are and the of the cholesterol is a Ceramide and from the of a POPC bilayer. Ceramide the of the with a Cholesterol and from the of the The lipids as from to and then to the of the bilayer. cholesterol, we the between long and the to the of the bilayer and the distribution cholesterol is with in and long to the of the is a in for the bilayer compared with the POPC cholesterol is into the the distributions are by an the distribution for cholesterol the bilayer with a large for cholesterol and from the bilayer for and is a small and cholesterol from the of the bilayer, and the leaflet from the bilayer to the and of the bilayer, cholesterol prefers to be to the of the bilayer with in with slow exchange between the two distributions for the between long and the membrane simulations. The to the for Cholesterol the of the bilayer. the can from to Cholesterol as it from the bilayer. cholesterol with the bilayer with an to cholesterol is in with a nearly The that the cholesterol with the bilayer ceramide and diacylglycerol are long and are well we the from the to the of the the POPC bilayer, there is a in as the ceramide or diacylglycerol the bilayer a In the bilayer, both lipids have a in the approximately from the bilayer which a This to the free energy for flip-flop the of the bilayer, the is to the the the of ceramide with one of the bilayer the thermodynamic and for lipid We estimate the half time for flip-flop for cholesterol to be approximately 20 and 30 in the POPC and bilayers. diacylglycerol, the half times are approximately 30 and 30 ms for the POPC and bilayers. The half time for ceramide flip-flop is approximately 10 ms in the POPC bilayer and 30 s in the bilayer. lipids have more in than their in the bilayer the lipids from into their in the bilayer to to in a larger for ceramide and a from the bilayer the with the bilayer, and the lipid becomes Ceramide and diacylglycerol in the as with the bilayer cholesterol, is by the in from approximately to the distributions for the bilayer and from the bilayer and the The in the for cholesterol is for the bilayer than the POPC bilayer, ceramide and diacylglycerol have for both bilayers. The free energy of a lipid and in is the free energy for the free energy in as we as the free energy for a lipid to from a bilayer to a POPC which is Cholesterol has a preference for the bilayer compared with the POPC bilayer, with a of has a preference for the POPC bilayer compared with the bilayer ceramide has a preference for the bilayer We the free energy for cholesterol, ceramide, and diacylglycerol translocation and in the two model membranes. of small bilayer to the local concentration to lipid flip-flop in a bilayer and a POPC bilayer. The bilayer both and more ordered than the POPC bilayer. lipids, the free energy for flip-flop for the bilayer compared with the bilayer, and the rate for of the in of translocation across the and bilayer. lipids of flip-flop in the bilayer compared with the bilayer, with and of for cholesterol, ceramide, and We that cholesterol has the rate of flip-flop in the bilayer, compared with ceramide and In the POPC bilayer, the rate for flip-flop the cholesterol diacylglycerol to the of different model systems, and diacylglycerol and ceramide, different with which affect the flip-flop Cholesterol flip-flop is the of the with rate from hours S. 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Devaux P.F. of ceramide and in the liquid ordered Biol. 2009; PubMed Scopus Google Scholar). This in to and which both flip-flop in bilayers with cholesterol A. I. F. F. Devaux P.F. of ceramide and in the liquid ordered Biol. 2009; PubMed Scopus Google Scholar). a it is to the in flip-flop these of that ceramide flip-flop in a bilayer is than in a liquid-ordered bilayer, we a half time of 30 s in the liquid-ordered which is than the A. I. F. F. Devaux P.F. of ceramide and in the liquid ordered Biol. 2009; PubMed Scopus Google Scholar). In an membrane, estimated to from the outer to on the timescale of a D. transbilayer of and to of membrane PubMed Scopus Google Scholar). diacylglycerol to across on a timescale of than acid transbilayer and of diacylglycerol are involved in the of a of acid by Biol. Chem. Full Text PDF PubMed Google Scholar). the half time for to be approximately 10 ms in The and transbilayer movement of diacylglycerols in Biol. Chem. Full Text PDF PubMed Google Scholar). it is to the and into lipid flip-flop is the for cholesterol, ceramide, and diacylglycerol translocation across two membranes with to both the of to the lipid and The free energy for flip-flop the the of for lipids. a mechanism for lipids in both as to a mechanism that has been for flip-flop of of and pore Chem. 2006; PubMed Scopus Google Scholar). The lipids are as long as half the bilayer the bilayer there are other to the free which the mechanism be The bilayer which is the process of flip-flop and to the energy specific be using bilayer or the free energies for lipid between the and POPC we for lipids. Cholesterol a large which a for cholesterol into bilayer domains over bilayer the that cholesterol with saturated phospholipids and The preference of cholesterol for more ordered and rigid membranes with cholesterol concentration is important for passive cholesterol trafficking from the with cholesterol the to the membrane G. are and Rev. Mol. Cell Biol. 2008; 9: PubMed Scopus Google Scholar). In to cholesterol, ceramide and diacylglycerol have relatively small which a preference for the POPC and bilayers. The between for diacylglycerol and ceramide be to diacylglycerol one unsaturated ceramide has two saturated The of that ceramide and diacylglycerol have a preference to with raft domains over It shown that both ceramide and diacylglycerol are to displace cholesterol from liquid-ordered domains and form more rigid domains (9London Megha E. Ceramide selectively displaces cholesterol from ordered lipid domains (rafts): implications for lipid raft structure and function.J. Biol. Chem. 2004; 279: 9997-10004Abstract Full Text Full Text PDF PubMed Scopus (368) Google Scholar). is concentration a ceramide displace a cholesterol from the a concentration of ceramide the domain forming a more rigid and ordered It is cholesterol have a preference for the ceramide domain and that ceramide have a preference for the to ceramide and diacylglycerol are a concentration (approximately (13Hannun Y.A. Obeid L.M. Principles of bioactive lipid signalling: lessons from sphingolipids.Nat. Rev. Mol. Cell Biol. 2008; 9: 139-150Crossref PubMed Scopus (2484) Google Scholar) and in rafts, which be important for signaling. such as sphingomyelinase, the local concentration of ceramide and a signaling of the of in are by the relatively large for flip-flop of the lipids in the bilayer, in which lipid dynamics are The times are to the lateral of lipids, problem is by the of of the lipid and two for lipids or cholesterol in two different are as the lipid is into and pore formation in and lipid the of Chem. 7: PubMed Scopus Google Scholar). It is that the the in The large in the for ceramide and diacylglycerol between the in the bilayer and the lipid in as well as the large in the for cholesterol in the bilayer using different of to the to a for the of of more more C. R. of properties in of molecular in lipid Chem. 7: PubMed Scopus Google Scholar). free energy of lipids in bilayers are and the is the state of the in the in as well as in free energy and more to be on more complex of for and in are which are to The for ceramide, diacylglycerol, and cholesterol in a with the and for the which more The important we are the in free which We that the free energy we for cholesterol flip-flop using the to using the S. Cholesterol from free energy Phys. Chem. B. 2010; PubMed Scopus Google Scholar). The location and dynamics of signaling lipids is to their function, of the signaling We lack a understanding of both the cellular localization of many lipids and the that their We to the and of flip-flop for important lipids, as well as the free energies for the in and POPC bilayers. the we of the specific molecular for the free energy including lipid membrane and molecular diacylglycerol, and ceramide have energy for flip-flop in the bilayer than the POPC bilayer that into of translocation across the bilayer. flip-flop in membrane can be from the of the bilayer, which from the to with the lipid and the of the Cholesterol to have a large preference for the bilayer compared with the POPC bilayer, which that cholesterol can be in raft domains both and Ceramide and diacylglycerol across the bilayer more than across the POPC bilayer, both have a relatively small between the two bilayers or nearly equal preference for both which be important for their signaling to the of lipid membranes.

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