Skip to main content
SpringerLink
Log in

Efficient Exploration of Membrane-Associated Phenomena at Atomic Resolution

  • Published:
The Journal of Membrane Biology Aims and scope Submit manuscript

Abstract

Biological membranes constitute a critical component in all living cells. In addition to providing a conducive environment to a wide range of cellular processes, including transport and signaling, mounting evidence has established active participation of specific lipids in modulating membrane protein function through various mechanisms. Understanding lipid–protein interactions underlying these mechanisms at a sufficiently high resolution has proven extremely challenging, partly due to the semi-fluid nature of the membrane. In order to address this challenge computationally, multiple methods have been developed, including an alternative membrane representation termed highly mobile membrane mimetic (HMMM) in which lateral lipid diffusion has been significantly enhanced without compromising atomic details. The model allows for efficient sampling of lipid–protein interactions at atomic resolution, thereby significantly enhancing the effectiveness of molecular dynamics simulations in capturing membrane-associated phenomena. In this review, after providing an overview of HMMM model development, we will describe briefly successful application of the model to study a variety of membrane processes, including lipid-dependent binding and insertion of peripheral proteins, the mechanism of phospholipid insertion into lipid bilayers, and characterization of optimal tilt angle of transmembrane helices. We conclude with practical recommendations for proper usage of the model in simulation studies of membrane processes.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2
Fig. 3
Fig. 4
Fig. 5
Fig. 6
Fig. 7
Fig. 8
Fig. 9
Fig. 10
Fig. 11
Fig. 12

Similar content being viewed by others

References

  • Andersen OS, Keoppe RE II (2007) Bilayer thickness and membrane protein function: an energetic perspective. Annu Rev Biophys Biomol Struct 36:107–130

    Article  CAS  PubMed  Google Scholar 

  • Anthis NJ, Wegener KL, Ye F, Kim C, Goult BT, Lowe ED, Vakonakis I, Bate N, Critchley DR, Ginsberg MH, Campbell ID (2009) The structure of an integrin/talin complex reveals the basis of inside-out signal transduction. EMBO J 28:3623–3632

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  • Arcario MJ, Tajkhorshid E (2014) Membrane-induced structural rearrangement and identification of a novel membrane anchor in Talin F2F3. Biophys J 107(9):2059–2069. doi:10.1016/j.bpj.2014.09.022

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Arcario MJ, Ohkubo YZ, Tajkhorshid E (2011) Capturing spontaneous partitioning of peripheral proteins using a biphasic membrane-mimetic model. J Phys Chem B 115:7029–7037

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  • Ayton GS, Voth GA (2009) Systematic multiscale simulation of membrane protein systems. Curr Opin Struct Biol 19:138–144

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Ayton GS, Lyman E, Voth GA (2010) Hierarchical coarse-graining strategy for protein-membrane systems to access mesoscopic scales. Faraday Discuss 144:347–357

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  • Baylon JL, Lenov IL, Sligar SG, Tajkhorshid E (2013) Characterizing the membrane-bound state of cytochrome P450 3A4: structure, depth of insertion, and orientation. J Am Chem Soc 135(23):8542–8551. doi:10.1021/ja4003525

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  • Bernèche S, Nina M, Roux B (1998) Molecular dynamics simulation of melittin in a dimyristoylphosphatidylcholine bilayer membrane. Biophys J 75:1603–1618

    Article  PubMed Central  PubMed  Google Scholar 

  • Blanchard AE, Arcario MJ, Schulten K, Tajkhorshid E (2014) A highly tilted membrane configuration for the pre-fusion state of synaptobrevin. Biophys J 107:2112–2121. doi:10.1016/j.bpj.2014.09.013

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Borbat P, Ramlall TF, Freed JH, Eliezer D (2006) Inter-helix distances in lysophospholipid micelle-bound \(\alpha\)-synuclein from pulsed ESR measurements. J Am Chem Soc 128:10,004–10,005. doi:10.1021/ja063122l

    Article  CAS  Google Scholar 

  • Bowen M, Brunger AT (2006) Conformation of the synaptobrevin transmembrane domain. Proc Natl Acad Sci USA 103:8378–8383

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  • Braun AR, Sachs JN (2015) \(\alpha\)-synuclein reduces tension and increases undulations in simulations of small unilamella vesicles. Biophys J 108(8):1848–1851. doi:10.1016/j.bpj.2015.03.029

    Article  CAS  PubMed  Google Scholar 

  • Braun AR, Sevcsik E, Chin P, Rhoades E, Tristram-Nagle S, Sachs JN (2012) \(\alpha\)-synuclein induces both positive mean curvature and negative gaussian curvature in membranes. J Am Chem Soc 134:2613–2620. doi:10.1021/ja208316h

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  • Braun AR, Lacy MM, Ducas VC, Rhoades E, Sachs JN (2014) \(\alpha\)-Synuclein-induced membrane remodeling is driven by binding affinity, partition depth, and interleaflet order asymmetry. J Am Chem Soc 136(28):9962–9972. doi:10.1021/ja5016958

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  • Brunger AT (2005) Structure and function of SNARE and SNARE-interacting proteins. Quart Rev Biophys 38:1–47

    Article  CAS  Google Scholar 

  • Brunger A, Weninger K, Bowen M, Chu S (2009) Single-molecule studies of the neuronal SNARE fusion machinery. Annu Rev Biochem 78:903–28

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  • Bu L, Im W, Brooks CL III (2007) Membrane assembly of simple helix homo-oligomers studied via molecular dynamics simulations. Biophys J 92:854–863

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  • Bucher D, Hsu YH, Mouchlis VD, Dennis EA, McCammon JA (2013) Insertion of the Ca\(^{2+}\)-independent phospholipase a\(_2\) into a phospholipid bilayer via coarse-grained and atomistic molecular dynamics simulations. PLoS Comput Biol 9(7):e1003156. doi:10.1371/journal.pcbi.1003156

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  • Burré J, Vivona S, Diao J, Sharma M, Brunger AT, Südhof TC (2013) Properties of native brain \(\alpha\)-synuclein. Nature 498:E4–E6. doi:10.1038/nature12125

    Article  PubMed Central  PubMed  CAS  Google Scholar 

  • Campbell ID, Ginsberg MH (2004) The talin-tail interaction places integrin activation on FERM ground. Trends Biochem Sci 29:429–435

    Article  CAS  PubMed  Google Scholar 

  • Charras GT, Williams BA, Sims SM, Horton MA (2004) Estimating the sensitivity of mechanosensitive ion channels to membrane strain and tension. Biophys J 87:2870–2884

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  • Chen J, Im W, Brooks CL III (2006) Balancing solvation and intramolecular interactions: toward a consistent generalized Born force field. J Am Chem Soc 128:3728–3736

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  • Colina CM, Venkateswarlu D, Duke R, Perera L, Pedersen LG (2006) What causes the enhancement of activity of factor VIIa by tissue factor? J Thromb Haem 4:2726–2729

    Article  CAS  Google Scholar 

  • Critchley DR (2009) Biochemical and structural properties of the integrin-associated cytoskeletal protein talin. Annu Rev Biophys 28:235–254

    Article  CAS  Google Scholar 

  • Daigle R, Rousseau JA, Guertin M, Lagüe P (2009) Theoretical investigations of nitric oxide channeling in Mycobacterium tuberculosis truncated hemoglobin N. Biophys J 97(11):2967–2977. doi:10.1016/j.bpj.2009.09.006

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  • Denisov IG, Grinkova YV, Lazarides AA, Sligar SG (2004) Directed self-assembly of monodisperse phospholipid bilayer nanodiscs with controlled size. J Am Chem Soc 126:3477–3487

    Article  CAS  PubMed  Google Scholar 

  • Denisov IG, Grinkova YV, Baylon JL, Tajkhorshid E, Sligar SG (2015) Mechanism of drug-drug interactions mediated by human cytochrome P450 CYP3A4 monomer. Biochemistry 54(13):2227–2239. doi:10.1021/acs.biochem.5b00079

    Article  CAS  PubMed  Google Scholar 

  • Dietrich C, Goldmann W, Sackmann E, Isenberg G (1993) Interaction of NBD-talin with lipid monolayers. FEBS Lett 324:37–40

    Article  CAS  PubMed  Google Scholar 

  • Drescher M, Veldhuis G, van Rooijen BD, Milikisyants S, Subramaniam V, Huber M (2008) Antiparallel arrangement of the helices of vesicle-bound \(\alpha\)-synuclein. J Am Chem Soc 130:7796–7797. doi:10.1021/ja801594s

    Article  CAS  PubMed  Google Scholar 

  • Durrieu MP, Bond PJ, Sansom MSP, Lavery R, Baaden M (2009) Coarse-grain simulations of the R-SNARE fusion protein in its membrane environment detect long-lived conformational sub-states. ChemPhysChem 10:1548–1552

    Article  CAS  PubMed  Google Scholar 

  • Einstein A (1905) Über die von der molekularkinetischen Theorie der Wärme geforderte Bewegung von in ruhenden Flüssigkeiten suspendierten Teilchen. Ann d Phys 17:549–560. doi:10.1002/andp.19053220806

    Article  CAS  Google Scholar 

  • Elliott PR, Goult BT, Kopp PM, Bate N, Grossmann JG, Roberts GC, Critchley DR, Barsukov IL (2010) The structure of the talin head reveals a novel extended conformation of the FERM domain. Structure 18:1289–1299

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  • Engelman DM (2005) Membranes are more mosaic than fluid. Nature 438:578–580. doi:10.1038/nature04394

    Article  CAS  PubMed  Google Scholar 

  • Fagerberg L, Jonasson K, von Heijne G, Uhlén M, Berglund L (2010) Prediction of the human membrane proteome. Proteomics 10(6):1141–1149. doi:10.1002/pmic.200900258

    Article  CAS  PubMed  Google Scholar 

  • Falls LA, Furie BC, Jacobs M, Furie B, Rigby AC (2001) The \(\omega\)-loop region of the human prothrombin \(\gamma\)-carboxyglutamic acid domain penetrates anionic phospholipid membranes. J Biol Chem 276:23,895–23,902

    Article  CAS  Google Scholar 

  • Fasshauer D, Otto H, Eliason WK, Jahn R, Brunger AT (1997) Structural changes are associated with soluble N-ethylmaleimide-sensitive fusion protein attachment protein receptor complex formation. J Biol Chem 272:28,036–28,041

    Article  CAS  Google Scholar 

  • Feig M, Brooks CL III (2004) Recent advances in the development and application of implicit solvent models in biomolecule simulations. Curr Opin Struct Biol 14:217–224

    Article  CAS  PubMed  Google Scholar 

  • Felding-Habermann B, Lerner RA, Lillo A, Zhuang S, Weber MR, Arrues S, Gao C, Mao S, Saven A, Janda KD (2004) Combinatorial antibody libraries from cancer patients yield ligand-mimetic Arg-Gly-Asp-containing immunoglobulins that inhibit breast cancer metastasis. Proc Natl Acad Sci USA 101:17,210–17,215

    Article  CAS  Google Scholar 

  • Fischer S, Nagel RL, Bookchin RM, Roth EF Jr, Tellez-Nagel I (1975) The binding of hemoglobin to membranes of normal and sickle erythrocytes. Biochim Biophys Acta Biomembr 375(3):422–433. doi:10.1016/0005-2736(75)90357-0

    Article  CAS  Google Scholar 

  • Fogarty JC, Arjunwadkar M, Pandit SA, Pan J (2015) Atomically detailed lipid bilayer models for the interpretation of small angle neutron and X-ray scattering data. Biochim Biophys Acta Biomembr 1848(2):662–672. doi:10.1016/j.bbamem.2014.10.041

    Article  CAS  Google Scholar 

  • Gennis RB (1989) Biomembranes: molecular structure and function. Springer, New York

    Book  Google Scholar 

  • Georgieva ER, Ramlall TF, Borbat PP, Freed JH, Eliezer D (2008) Membrane-bound alpha-synuclein forms an extended helix: long-distance pulsed ESR measurements using vesicles, bicelles and rod-like micelles. J Am Chem Soc 130:12,856–12,857. doi:10.1021/ja804517m

    Article  CAS  Google Scholar 

  • Georgieva ER, Ramlall TF, Borbat PP, Freed JH, Eliezer D (2010) The lipid-binding domain of wild type and mutant \(\alpha\)-synuclein: compactness and interconversion between the broken and extended helix forms. J Biol Chem 285:28,261–28,274. doi:10.1074/jbc.M110.157214

    Article  CAS  Google Scholar 

  • Goult BT, Bate N, Anthis NJ, Wegener KL, Gingras AR, Patel B, Barsukov IL, Campbell ID, Roberts GC, Critchley DR (2009) The structure of an interdomain complex that regulates talin activity. J Biol Chem 284:15,097–15,106

    Article  CAS  Google Scholar 

  • Grafmüller A, Lipowsky R, Knecht V (2013) Effect of tension and curvature on the chemical potential of lipids in lipid aggregates. Phys Chem Chem Phys 15(3):876–881. doi:10.1039/c2cp43018e

    Article  PubMed  Google Scholar 

  • Grecco HE, Schmick M, Bastiaens PIH (2011) Signaling from the living plasma membrane. Cell 144(6):897–909. doi:10.1016/j.cell.2011.01.029

    Article  CAS  PubMed  Google Scholar 

  • Grubmüller H, Heymann B, Tavan P (1996) Ligand binding and molecular mechanics calculation of the streptavidin-biotin rupture force. Science 271:997–999

    Article  PubMed  Google Scholar 

  • Guengerich PF (1999) Cytochrome P450 3A4: regulation and role in drug metabolism. Annu Rev Pharmacol Toxicol 39:1–17

    Article  CAS  PubMed  Google Scholar 

  • Hui E, Johnson CP, Yao J, Dunning FM, Chapman ER (2009) Synaptotagmin-mediated bending of target membrane is a critical step in Ca\(^{2+}\)-regulated fusion. Cell 138:709–721

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  • Hynes RO (2002) Integrins: bidirectional, allosteric signaling machines. Cell 110:673–687

    Article  CAS  PubMed  Google Scholar 

  • Im W, Brooks CL III (2005) Interfacial folding and membrane insertion of designed peptides studied by molecular dynamics simulations. Proc Natl Acad Sci USA 102:6771–6776

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  • Ingólfsson HI, Melo MN, van Eerden FJ, Arnarez C, López CA, Wassenaar TA, Periole X, De Vries AH, Tieleman DP, Marrink SJ (2014) Lipid organization of the plasma membrane. J Am Chem Soc 136(14):14,554–14,559. doi:10.1021/ja507832e

    Article  CAS  Google Scholar 

  • Isenberg G, Goldmann WH (1998) Peptide-specific antibodies localize the major lipid binding sites of talin dimers to oppositely arranged N-terminal 47 kDa subdomains. FEBS Lett 426:165–170

    Article  CAS  PubMed  Google Scholar 

  • Izrailev S, Stepaniants S, Balsera M, Oono Y, Schulten K (1997) Molecular dynamics study of unbinding of the avidin-biotin complex. Biophys J 72:1568–1581

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  • Izvekov S, Voth GA (2005) Multiscale coarse graining of liquid-state systems. J Chem Phys 123(134):105

    Google Scholar 

  • Jahn R, Scheller RH (2006) SNAREs—engines for membrane fusion. Nat Rev Mol Cell Biol 7:631–643

    Article  CAS  PubMed  Google Scholar 

  • Jao CC, Der-Sarkissian A, Chen J, Langen R (2004) Structure of membrane-bound \(\alpha\)-synuclein studied by site-directed spin-labeling. Proc Natl Acad Sci USA 101:8331–8336. doi:10.1073/pnas.0400553101

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  • Jao CC, Hegde BG, Chen J, Haworth IS, Langen R (2008) Structure of membrane-bound \(\alpha\)-synuclein from site-directed spin labeling and computational refinement. Proc Natl Acad Sci USA 105(50):19,666–19,671. doi:10.1073/pnas.0807826105

    Article  CAS  Google Scholar 

  • Jo S, Kim T, Iyer VG, Im W (2008) CHARMM-GUI: a web-based graphical user interface for CHARMM. J Comp Chem 29:1859–1865

    Article  CAS  Google Scholar 

  • Jo S, Lim JB, Klauda JB, Im W (2009) CHARMM-GUI membrane builder for mixed bilayers and its application to yeast membranes. Biophys J 97:50–58

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  • Kalli AC, Wegener KL, Goult BT, Anthis NJ, Campbell ID, Sansom MS (2010) The structure of the talin/integrin complex at a lipid bilayer: an NMR and MD simulation study. Structure 18:1280–1288

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  • Kalli AC, Campbell ID, Sansom MSP (2013) Conformational changes in talin on binding to anionic phospholipid membranes facilitate signaling by integrin transmembrane helices. PLoS Comput Biol 9(10):e1003316. doi:10.1371/journal.pcbi.1003316

    Article  PubMed Central  PubMed  Google Scholar 

  • Khalid S, Bond PJ (2013) Multiscale molecular dynamics simulations of membrane proteins. Methods Mol Biol 924:635–657

    Article  CAS  PubMed  Google Scholar 

  • Klauda JB, Brooks BR, Pastor RW (2006) Dynamical motions of lipids and a finite size effect in simulations of bilayers. J Chem Phys 125(144):710. doi:10.1063/1.2354486

    Google Scholar 

  • Klose C, Surma MA, Simons K (2013) Organellar lipidomics—background and perspectives. Curr Opin Cell Biol 25:406–413

    Article  CAS  PubMed  Google Scholar 

  • Kohout SC, Corbalán-García S, Gómez-Fernández JC, Falke JJ (2003) C2 domain of protein kinase C\(\alpha\): elucidation of the membrane docking surface by site-directed fluorescence and spin labeling. Biochemistry 42:1254–1265

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  • Kumar S, Bouzida D, Swendsen RH, Kollman PA, Rosenberg JM (1992) The weighted histogram analysis method for free-energy calculations on biomolecules I. The method. J Comput Chem 13:1011–1021

    Article  CAS  Google Scholar 

  • Kweon DH, Kim CS, Shin YK (2003) Regulation of neuronal SNARE assembly by the membrane. Nat Struct Biol 10:440–447

    Article  CAS  PubMed  Google Scholar 

  • Lagüe P, Roux B, Roux RW (2005) Molecular dynamics simulations of the influenza hemagglutinin fusion peptide in micelles and bilayers: conformational analysis of peptide and lipids. J Mol Biol 354:1129–1141

    Article  PubMed  CAS  Google Scholar 

  • Lai CL, Landgraf KE, Voth GA, Falke JJ (2010) Membrane docking geometry and target lipid stoichiometry of membrane-bound PKC C2 domain: a combined molecular dynamics and experimental study. J Mol Biol 402:301–310

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  • Larsson P, Kasson PM (2013) Lipid tail protrusion in simulations predicts fusogenic activity of influenza fusion peptide mutants and conformational models. PLoS Comput Biol 9(e1002):950

    Google Scholar 

  • Leech J, Prins J, Hermans J (1996) SMD: visual steering of molecular dynamics for protein design. IEEE Comput Sci Eng 3(4):38–45

    Article  CAS  Google Scholar 

  • Lemmon MA (2008) Membrane recognition by phospholipid-binding domains. Nat Rev Mol Cell Biol 9:99–111

    Article  CAS  PubMed  Google Scholar 

  • Liddington RC, Ginsberg MH (2002) Integrin activation takes shape. J Cell Biol 158:833–839

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  • Lin SW, Kochendoerfer GG, Carrol KS, Wang D, Mathies RA, Sakmar TP (1998) Mechanisms of spectral tuning in blue cone visual pigments. Visible and Raman spectroscopy of blue-shifted rhodopsin mutants. J Biol Chem 273:24,583–24,591

    Article  CAS  Google Scholar 

  • Lindahl E, Sansom MSP (2008) Membrane proteins: molecular dynamics simulations. Curr Opin Struct Biol 18:425–431

    Article  CAS  PubMed  Google Scholar 

  • Lokappa SB, Ulmer TS (2011) Alpha-synuclein populates both elongated and broken helix states on small unilamellar vesicles. J Biol Chem 286(24):21450–21457. doi:10.1074/jbc.M111.224055

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  • Lokappa SB, Suk JE, Balasubramanian A, Samanta S, Situ AJ, Ulmer TS (2014) Sequence and membrane determinants of the random coil-helix transition of \(\alpha\)-synuclein. J Mol Biol 426(10):2130–2144. doi:10.1016/j.jmb.2014.02.024

    Article  CAS  PubMed  Google Scholar 

  • Lomize MA, Pogozheva ID, Joo H, Mosberg HI, Lomize AL (2012) OPM database and ppm web server: resources for positioning of proteins in membranes. Nucleic Acids Res 40:D370–376

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  • Ma Y, Qin J, Plow E (2007) Platelet integrin \(\alpha _{IIb}\beta _{3}\): activation mechanisms. J Thromb Haemost 5:1345–1352

    Article  CAS  PubMed  Google Scholar 

  • MacCallum JL, Bennett WFD, Tieleman DP (2008) Distribution of amino acids in a lipid bilayer from computer simulations. Biophys J 94:3393–3404

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  • Mairbäurl H, Weber RE (2012) Oxygen transport by hemoglobin. Compr Physiol 2(2):1463–1489. doi:10.1002/cphy.c080113

    PubMed  Google Scholar 

  • Marrink SJ, Tieleman DP (2013) Perspective on the MARTINI model. Chem Soc Rev 42:6801–6822

    Article  CAS  PubMed  Google Scholar 

  • Marrink SJ, de Vries AH, Mark AE (2004) Coarse grained model for semiquantitative lipid simulations. J Phys Chem B 108:750–760

    Article  CAS  Google Scholar 

  • Marrink SJ, Risselada HJ, Yefimov S, Tieleman DP, de Vries AH (2007) The MARTINI force field: coarse grained model for biomolecular simulations. J Phys Chem B 111:7812–7824

    Article  CAS  PubMed  Google Scholar 

  • Martel V, Racaud-Sultan C, Dupe S, Marie C, Paulhe F, Galmiche A, Block MR, Albiges-Rizo C (2001) Conformation, localization, and integrin binding of talin depend on its interaction with phosphoinositides. J Biol Chem 276:21,217–21,227

    Article  CAS  Google Scholar 

  • Martens S, Kozlov MM, McMahon HT (2007) How synaptotagmin promotes membrane fusion. Science 316:1205–1208

    Article  CAS  PubMed  Google Scholar 

  • McCallum CD, Hapak RC, Neuenschwander PF, Morrissey JH, Johnson AE (1996) The location of the active site of blood coagulation factor VIIa above the membrane surface and its reorientation upon association with tissue factor. J Biol Chem 271:28168–28175

    Article  CAS  PubMed  Google Scholar 

  • McCallum CD, Su B, Neuenschwander PF, Morrissey JH, Johnson AE (1997) Tissue factor positions and maintains the factor VIIa active site far above the membrane surface even in the absence of the factor VIIa Gla domain - A fluorescence resonance energy transfer study. J Biol Chem 272:30160–30166

    Article  CAS  PubMed  Google Scholar 

  • McLean LR, Phillips MC (1981) Mechanism of cholesterol and phosphatidylcholine exchange or transfer between unilamellar vesicles. Biochemistry 20:2893–2900

    Article  CAS  PubMed  Google Scholar 

  • McNew JA, Weber T, Engelman DM, Söllner TH, Rothman JE (1999) The length of the flexible SNAREpin juxtamembrane region is a critical determinant of SNARE-dependent fusion. Mol Cell 4:415–421

    Article  CAS  PubMed  Google Scholar 

  • Middleton ER, Rhoades E (2010) Effects of curvature and composition on \(\alpha\)-synuclein binding to lipid vesicles. Biophys J 99:2279–2288. doi:10.1016/j.bpj.2010.07.056

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  • Milani M, Pesce A, Ouellet Y, Ascenzi P, Guertin M, Bolognesi M (2001) Mycobacterium tuberculosis hemoglobin n displays a protein tunnel suited for O\(_2\) diffusion to the heme. EMBO J 20(15):3902–3909. doi:10.1093/emboj/20.15.3902

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  • Mizuno H, Fujimoto Z, Atoda H, Morita T (2001) Crystal structure of an anticoagulant protein in complex with the Gla domain of factor X. Proc Natl Acad Sci USA 98:7230–7234

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  • Mondal J, Zhu X, Cui Q, Yethiraj A (2010) Sequence-dependent interaction of \(\beta\)-peptides with membranes. J Phys Chem B 114:13,585–13,592

    Article  CAS  Google Scholar 

  • Monticelli L, Kandasamy SK, Periole X, Larson RG, Tieleman DP, Marrink SJ (2008) The MARTINI coarse grained forcefield: extension to proteins. J Chem Theory Comput 4:819–834

    Article  CAS  PubMed  Google Scholar 

  • Mosbaek CR, Nolan D, Persson E, Svergun DI, Bukrinsky JT, Vestergaard B (2010) Extensive small-angle X-ray scattering studies of blood coagulation factor VIIa reveal interdomain felxibility. Biochemistry 49:9739–9745

    Article  CAS  PubMed  Google Scholar 

  • Moser M, Legate KR, Zent R, Fässler R (2009) The tail of integrins, talin, and kindlins. Science 324:895–899

    Article  CAS  PubMed  Google Scholar 

  • Mouritsen OG (2005) Life-as a matter of fat, 1st edn. Springer, Berlin

    Google Scholar 

  • Muguruma M, Nishimuta S, Tomisaka Y, Ito T, Matsumura S (1995) Organisation of the functional domains in membrane cytoskeletal protein talin. J Biochem 117:1036–1042

    CAS  PubMed  Google Scholar 

  • Nelsestuen GL (1999) Enhancement of vitamin-K-dependent protein function by modification of the \(\gamma\)-carboxyglutamic acid domain: Studies of protein C and factor VII. Trends Cardiovasc Med 9:162–167

    Article  CAS  PubMed  Google Scholar 

  • Ngatchou AN, Kisler K, Fang Q, Walter AM, Zhao Y, Bruns D, Sørensen JB, Lindau M (2010) Role of synaptobrevin C terminus in fusion pore formation. Proc Natl Acad Sci USA 107:18,463–18,468

    Article  CAS  Google Scholar 

  • Nichols JW, Pagano RE (1981) Kinetics of soluble lipid monomer diffusion between vesicles. Biochemistry 20(10):2783–2789. doi:10.1021/bi00513a012

    Article  CAS  PubMed  Google Scholar 

  • Ohkubo YZ, Tajkhorshid E (2008) Distinct structural and adhesive roles of Ca\(^{2+}\) in membrane binding of blood coagulation factors. Structure 16:72–81

    Article  CAS  PubMed  Google Scholar 

  • Ohkubo YZ, Pogorelov TV, Arcario MJ, Christensen GA, Tajkhorshid E (2012) Accelerating membrane insertion of peripheral proteins with a novel membrane mimetic model. Biophys J 102:2130–2139. doi:10.1016/j.bpj.2012.03.015

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  • Oliveira A, Singh S, Bidon-Chanal A, Forti F, Martí MA, Boechi L, Estrin DA, Dikshit KL, Luque FJ (2012) Role of PheE15 gate in ligand entry and nitric oxide detoxification function of Mycobacterium tuberculosis truncated hemoglobin N. PLoS One 7(11):e49291. doi:10.1371/journal.pone.0049291

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  • Pathania R, Navani NK, Rajamohan G, Dikshit KL (2002) Mycobacterium tuberculosis hemoglobin HbO associates with membranes and stimulates cellular respiration of recombinant Escherichia coli. J Biol Chem 277(18):15293–15302. doi:10.1074/jbc.M111478200

    Article  CAS  PubMed  Google Scholar 

  • Perlmutter JD, Braun AR, Sachs JN (2009) Curvature dynamics of \(\alpha\)-synuclein familial parkinson disease mutants. J Biol Chem 284:7177–7189. doi:10.1074/jbc.M808895200

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  • Phillips JC, Braun R, Wang W, Gumbart J, Tajkhorshid E, Villa E, Chipot C, Skeel RD, Kale L, Schulten K (2005) Scalable molecular dynamics with NAMD. J Comp Chem 26:1781–1802

    Article  CAS  Google Scholar 

  • Pogorelov TV, Vermaas JV, Arcario MJ, Tajkhorshid E (2014) Partitioning of amino acids into a model membrane: capturing the interface. J Phys Chem B 118:1481–1492. doi:10.1021/jp4089113

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  • Rao JN, Jao CC, Hegde BG, Langen R, Ulmer TS (2010) A combinatorial NMR and EPR apporoach for evaluating the structural ensemble of partially folded proteins. J Am Chem Soc 132:8657–8668. doi:10.1021/ja100646t

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  • Ratnikov B, Partridge A, Ginsberg M (2005) Integrin activation by talin. J Thromb Haemost 3:1783–1790

    Article  CAS  PubMed  Google Scholar 

  • Rees D, Ades SE, Singer S, Hynes RO (1990) Sequence and domain structure of talin. Nature 347:685–689

    Article  CAS  PubMed  Google Scholar 

  • Rhéault JF, Gagné E, Guertin M, Lamoureux G, Auger M, Lagüe P (2015) Molecular model of hemoglobin N from Mycobacterium tuberculosis bound to lipid bilayers: a combined spectroscopic and computational study. Biochemistry 54(11):2073–2084. doi:10.1021/bi5010624

    Article  PubMed  CAS  Google Scholar 

  • Risselada H, Kutzner C, Grubmuller H (2011) Caught in the act: visualization of SNARE-mediated fusion events in molecular detail. ChemBioChem 12:1049–1055

    Article  CAS  PubMed  Google Scholar 

  • Robotta M, Braun P, van Rooijen B, Subramaniam V, Huber M, Drescher M (2011) Direct evidence of coexisting horseshoe and extended helix conformations of membrane-bound alpha-synuclein. ChemPhysChem 12:267–269. doi:10.1002/cphc.201000815

    Article  CAS  PubMed  Google Scholar 

  • Saltel F, Mortier E, Hytönen VP, Jacquier MC, Zimmermann P, Vogel V, Liu W, Wehrle-Haller B (2009) New PI(4,5)P\(_{2}\)- and membrane proximal integrin-binding motifs in the talin head control \(\beta\)3-integrin clustering. J Cell Biol 187:715–731

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  • Sampaio JL, Gerla MJ, Klosea C, Ejsingb CS, Beugc H, Simonsa K, Shevchenko A (2011) Membrane lipidome of an epithelial cell line. Proc Natl Acad Sci USA 108:1903–1907

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  • Schleinkofer K, Sudarko Winn PJ, Lüdemann SK, Wade RC (2005) Do mammalian cytochrome P450s show multiple ligand access pathways and ligand channelling? EMBO Rep 6(6):584–589

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  • Seelig A, Blatter XL, Frentzel A, Isenberg G (2000) Phospholipid binding of synthetic talin peptides provides evidence for an intrinsic membrane anchor of talin. J Biol Chem 275:17,954–17,961

    Article  CAS  Google Scholar 

  • Shattil SJ, Kim C, Ginsberg MH (2010) The final steps of integrin activation: the end game. Nat Rev Mol Cell Biol 11:288–300

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  • Shaw DE, Deneroff MM, Dror RO, Kuskin JS, Larson RH, Salmon JK, Young C, Batson B, Bowers KJ, Chao JC, Eastwood MP, Gagliardo J, Grossman JP, Ho CR, Ierardi DJ, Kolossváry I, Klepeis JL, Layman T, McLeavey C, Moraes MA, Mueller R, Priest EC, Shan Y, Spengler J, Theobald M, Towles B, Wang SC (2008) Anton, a special-purpose machine for molecular dynamics simulation. Commun ACM 51:91–97

    Article  Google Scholar 

  • Shaw DE, Grossman J, Bank JA, Batson B, Butts JA, Chao JC, Deneroff MM, Dror RO, Even A, Fenton CH et al (2014) Anton 2: raising the bar for performance and programmability in a special-purpose molecular dynamics supercomputer. Proceedings of the international conference for high performance computing. Storage and analysis, IEEE Press, Networking, pp 41–53

  • Shelley JC, Shelley MY, Reeder RC, Bandyopadhyay S, Moore PB, Klein ML (2001) Simulations of phospholipids using a coarse grain model. J Phys Chem B 105:9785–9792

    Article  CAS  Google Scholar 

  • Shiva S, Brookes PS, Patel RP, Anderson PG, Darley-Usmar VM (2001) Nitric oxide partitioning into mitochondrial membranes and the control of respiration at cytochrome c oxidase. Proc Natl Acad Sci USA 98(13):7212–7217. doi:10.1073/pnas.131128898

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  • Singer S, Nicolson G (1972) The fluid mosaic model of the structure of cell membranes. Science 173:720–731

    Article  Google Scholar 

  • Singleton AB, Farrer M, Johnson J, Singleton A, Hague S, Kachergus J, Hulihan M, Peuralinna T, Dutra A, Nussbaum R, Lincoln S, Crawley A, Hanson M, Maraganore D, Adler C, Cookson MR, Muenter M, Baptista M, Miller D, Blancato J, Hardy J, Gwinn-Hardy K (2003) \(\alpha\)-synuclein locus triplication causes parkinson’s disease. Science 302:841. doi:10.1126/science.1090278

    Article  CAS  PubMed  Google Scholar 

  • Smirnova YG, Marrink SJ, Lipowsky R, Knecht V (2010) Solvent-exposed tails as prestalk transition states for membrane fusion at low hydration. J Am Chem Soc 132(19):6710–6718. doi:10.1021/ja910050x

    Article  CAS  PubMed  Google Scholar 

  • Snider C, Jayasinghe S, Hristova K, White SH (2009) MPEx: a tool for exploring membrane proteins. Protein Sci 18:2624–2628

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  • Stein A, Weber G, Wahl MC, Jahn R (2009) Helical extension of the neuronal SNARE complex into the membrane. Nature 460:525–528

    PubMed Central  CAS  PubMed  Google Scholar 

  • Subczynski WK, Hyde JS (1983) Concentration of oxygen in lipid bilayers using a spin-label method. Biophys J 41(3):283–286. doi:10.1016/S0006-3495(83)84439-7

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  • Südhof TC (2004) The synaptic vesicle cycle. Annu Rev Neurosci 27:509–547

    Article  PubMed  CAS  Google Scholar 

  • Südhof TC, Rothman J (2009) Membrane fusion: grappling with SNARE and SM proteins. Science 323:474–477

    Article  PubMed Central  PubMed  CAS  Google Scholar 

  • Sutton RB, Fasshauer D, Jahn R, Brunger AT (1998) Crystal structure of a SNARE complex involved in synaptic exocytosis at 2.4 Å resolution. Nature 395:347–353

    Article  CAS  PubMed  Google Scholar 

  • Tadokoro S, Shattil SJ, Eto K, Tai V, Liddington RC, dePereda JM, Ginsberg MH, Calderwood DA (2003) Talin binding to integrin \(\beta\) tails: A final common step in integrin activation. Science 302:103–106

    Article  CAS  PubMed  Google Scholar 

  • Tempel M, Goldmann WH, Isenberg G, Sackmann E (1995) Interaction of the 47-kDa talin fragment and the 32-kDa vinculin fragment with acidic phospholipids: a computer analysis. Biophys J 69:228–241

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  • Tieleman DP, Marrink SJ (2006) Lipids out of equilibrium: energetics of desorption and pore mediated flip-flop. J Am Chem Soc 128:12,462–12,467. doi:10.1021/ja0624321

    Article  CAS  Google Scholar 

  • Torrie GM, Valleau JP (1977) Nonphysical sampling distributions in Monte Carlo free-energy estimation: umbrella sampling. J Comput Phys 23:187–199

    Article  Google Scholar 

  • Trexler AJ, Rhoades E (2009) \(\alpha\)-Synuclein binds large unilamellar vesicles as an extended helix. Biochemistry 48:2304–2306. doi:10.1021/bi900114z

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  • Ulmer TS, Bax A, Cole NB, Nussbaum RL (2005) Structure and dynamics of micelle-bound human alpha-synuclein. J Biol Chem 280:9595–9603

    Article  CAS  PubMed  Google Scholar 

  • van Meer G, de Kroon AIPM (2011) Lipid map of the mammalian cell. J Cell Sci 124(Pt 1):5–8. doi:10.1242/jcs.071233

    Article  PubMed  CAS  Google Scholar 

  • van Meer G, Voelker DR, Feigenson GW (2008) Membrane lipids: where they are and how they behave. Nat Rev Mol Cell Biol 9:112–124

    Article  PubMed Central  PubMed  CAS  Google Scholar 

  • Vanommeslaeghe K, Hatcher E, Acharya C, Kundu S, Zhong S, Shim J, Darian E, Guvench O, Lopes P, Vorobyov I, MacKerell AD Jr (2010) CHARMM general force field: a force field for drug-like molecules compatible with the CHARMM all-atom additive biological force fields. J Comput Chem 31(4):671–690

    PubMed Central  CAS  PubMed  Google Scholar 

  • Vermaas JV, Tajkhorshid E (2014a) Conformational heterogeneity of \(\alpha\)-synuclein in membrane. Biochim Biophys Acta Biomembr 1838(12):3107–3117. doi:10.1016/j.bbamem.2014.08.012

    Article  CAS  Google Scholar 

  • Vermaas JV, Tajkhorshid E (2014b) A microscopic view of phospholipid insertion into biological membranes. J Phys Chem B 118:1754–1764. doi:10.1021/jp409854w

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  • Waters EK, Yegneswaran S, Morrissey JH (2006) Raising the active site of factor VIIa above the membrane surface reduces its procoagulant activity but not factor VII autoactivation. J Biol Chem 281:26,062–26,068

    Article  CAS  Google Scholar 

  • Wegener KL, Partridge AW, Han J, Pickford AR, Liddington RC, Ginsberg MH, Campbell ID (2007) Structural basis of integrin activation by talin. Cell 128:171–182

    Article  CAS  PubMed  Google Scholar 

  • Williams PA, Cosme J, Ward A, Angove HC, Matak Vinković D, Jhoti H (2003) Crystal structure of human cytochrome P450 2C9 with bound warfarin. Nature 424(6947):464–8

    Article  CAS  PubMed  Google Scholar 

  • Wohlert J, Edholm O (2006) Dynamics in atomistic simulations of phospholipid membranes: nuclear magnetic resonance relaxation rates and lateral diffusion. J Chem Phys 125(204):703. doi:10.1063/1.2393240

    Google Scholar 

  • Wu Z, Schulten K (2014) Synaptotagmin’s role in neurotransmitter release likely involves Ca\(^{2+}\)-induced conformational transition. Biophys J 107:1156–1166

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  • Wu E, Cheng X, Jo S, Rui H, Song K, Dávila-Contreras E, Qi Y, Lee J, Monje-Galvan V, Venable R, Klauda J, Im W (2014) CHARMM-GUI membrane builder toward realistic biological membrane simulations. J Comput Chem 35(27):1997–2004. doi:10.1002/jcc.23702

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Yildirim MA, Goh KI, Cusick ME, Barabasi AL, Vidal M (2007) Drug-target network. Nat Biotechnol 25:1119–1126. doi:10.1038/nbt1338

    Article  CAS  PubMed  Google Scholar 

Download references

Acknowledgment

This work was supported in part by the National Institutes of Health (Grants R01-GM101048, R01-GM086749, U54-GM087519, and P41-GM104601 to E.T.) and XSEDE compute resources (Grant TG-MCA06N060 to E.T. and Grant TG-MCB130112 to T.V.P.). J.V.V. acknowledges support from the Sandia National Laboratories Campus Executive Program, which is funded by the Laboratory Directed Research and Development (LDRD) Program. Sandia is a multi-program laboratory managed and operated by Sandia Corporation, a wholly owned subsidiary of Lockheed Martin Corporation, for the US Department of Energy’s National Nuclear Security Administration under Contract No. DE-AC04-94AL85000, and previous support from the DOE CSGF Fellowship (DE-FG02-97ER25308). M.J.A. acknowledges past support from the NSF GRF Program. Z.W. acknowledges support from the NSF-funded Center of Physics in Living Cell (NSF PHY1430124). T.V.P. is grateful for the support from the Illinois Campus Research Board. T.V.P. was a Faculty Fellow of the National Center for Supercomputing Applications when this work was completed.

Conflicts of interest

The authors declare no conflicts of interest.

Compliance with Ethical Standards

This is a review of prior work funded publicly, and appropriate figures have been reused or adapted with permission from the original authors and publishers. The nature of the presented work is purely computational and does not include human or animal subjects.

Author information

Authors and Affiliations

  1. Department of Biochemistry, and Center for Biophysics and Computational Biology, Beckman Institute, University of Illinois at Urbana-Champaign, 405 N. Mathews Ave., Urbana, IL, 61801, USA

    Josh V. Vermaas, Javier L. Baylon, Mark J. Arcario, Melanie P. Muller, Zhe Wu, Taras V. Pogorelov & Emad Tajkhorshid

Authors
  1. Josh V. Vermaas
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Javier L. Baylon
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Mark J. Arcario
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Melanie P. Muller
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Zhe Wu
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Taras V. Pogorelov
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Emad Tajkhorshid
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Emad Tajkhorshid.

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Vermaas, J.V., Baylon, J.L., Arcario, M.J. et al. Efficient Exploration of Membrane-Associated Phenomena at Atomic Resolution. J Membrane Biol 248, 563–582 (2015). https://doi.org/10.1007/s00232-015-9806-9

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s00232-015-9806-9

Keywords

Search

Navigation