Skip to main content
SpringerLink
Log in
Book cover

Membrane Proteins Production for Structural Analysis pp 347–392Cite as

Foundations of Biomolecular Simulations: A Critical Introduction to Homology Modeling, Molecular Dynamics Simulations, and Free Energy Calculations of Membrane Proteins

  • Chapter
  • First Online:

  • 1805 Accesses

Abstract

We review foundations of biomolecular simulations that enable the study of membrane protein models with a particular focus on structure–function relationships and opportunities for drug design. A range of broadly used methods is presented comprising homology modeling, normal mode analysis, molecular dynamics simulations, and free energy calculations. These methods are illustrated with examples on several membrane protein systems, in particular ligand-gated ion channels such as the P2X receptors, the N-methyl-d-aspartate (NMDA) receptors, and the Cys-loop family of pentameric ion channels.

An erratum to this chapter can be found at http://dx.doi.org/10.1007/978-1-4939-0662-8_15

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

Chapter
USD   29.95
Price excludes VAT (USA)
  • Available as PDF
  • Read on any device
  • Instant download
  • Own it forever
eBook
USD   129.00
Price excludes VAT (USA)
  • Available as EPUB and PDF
  • Read on any device
  • Instant download
  • Own it forever
Softcover Book
USD   169.99
Price excludes VAT (USA)
  • Compact, lightweight edition
  • Dispatched in 3 to 5 business days
  • Free shipping worldwide - see info
Hardcover Book
USD   169.99
Price excludes VAT (USA)
  • Durable hardcover edition
  • Dispatched in 3 to 5 business days
  • Free shipping worldwide - see info

Tax calculation will be finalised at checkout

Purchases are for personal use only

Learn about institutional subscriptions

References

  • Abin-Carriquiry JA, Zunini MP, Cassels BK, Wonnacott S, Dajas F (2010) In silico characterization of cytisinoids docked into an acetylcholine binding protein. Bioorg Med Chem Lett 20(12):3683–3687

    CAS  PubMed  Google Scholar 

  • Adriouch S, Bannas P, Schwarz N, Fliegert R, Guse AH, Seman M, Haag F, Koch-Nolte F (2008) ADP-ribosylation at R125 gates the P2X7 ion channel by presenting a covalent ligand to its nucleotide binding site. FASEB J 22(3):861–869

    CAS  PubMed  Google Scholar 

  • Alberts IL, Nadassy K, Wodak SJ (1998) Analysis of zinc binding sites in protein crystal structures. Protein Sci 7:1700–1716

    CAS  PubMed Central  PubMed  Google Scholar 

  • Armstrong N, Gouaux E (2000) Mechanisms for activation and antagonism of an AMPA-sensitive glutamate receptor: crystal structures of the GluR2 ligand binding core. Neuron 28:165–181

    CAS  PubMed  Google Scholar 

  • Artali R, Bombieri G, Meneghetti F (2005) Docking of 6-chloropyridazin-3-yl derivatives active on nicotinic acetylcholine receptors into molluscan acetylcholine binding protein (AChBP). Farmaco 60(4):313–320

    CAS  PubMed  Google Scholar 

  • Aschrafi A, Sadtler S, Niculescu C, Rettinger J, Schmalzing G (2004) Trimeric architecture of homomeric P2X2 and heteromeric P2X1+2 receptor subtypes. J Mol Biol 342:333–343

    CAS  PubMed  Google Scholar 

  • Baaden M, Lavery R (2007) There’s plenty of room in the middle: multi-scale modelling of biological systems. In: de Brevern AG (ed) Recent advances in protein engineering. Research signpost, India, pp 173–195

    Google Scholar 

  • Babakhani A, Talley TT, Taylor P, McCammon JA (2009) A virtual screening study of the acetylcholine binding protein using a relaxed-complex approach. Comput Biol Chem 33(2):160–170

    CAS  PubMed Central  PubMed  Google Scholar 

  • Bahar I (1999) Dynamics of proteins and biomolecular complexes: inferring functional motions from structure. Rev Chem Eng 15:319–347

    CAS  Google Scholar 

  • Bahar I, Rader AJ (2005) Coarse-grained normal mode analysis in structural biology. Curr Opin Struct Biol 15:586–592

    CAS  PubMed Central  PubMed  Google Scholar 

  • Barrera NP, Ormond SJ, Henderson RM, Murrell-Lagnado RD, Edwardson JM (2005) Atomic force microscopy imaging demonstrates that P2X2 receptors are trimers but that P2X6 receptor subunits do not oligomerize. J Biol Chem 280:10759–10765

    CAS  PubMed  Google Scholar 

  • Bernèche S, Roux B (2001) Energetics of ion conduction through the K+ channel. Nature 414:73–77

    PubMed  Google Scholar 

  • Bocquet N, Prado deCL, Cartaud J, Neyton J, Le Poupon C, Taly A, Grutter T, Changeux J-P, Corringer P-J (2007) A prokaryotic proton-gated ion channel from the nicotinic acetylcholine receptor family. Nature 445(7123):116–119

    CAS  PubMed  Google Scholar 

  • Bocquet N, Nury H, Baaden M, Le Poupon C, Changeux JP, Delarue M, Corringer PJ (2009) X-ray structure of a pentameric ligand-gated ion channel in an apparently open conformation. Nature 457(7225):111–114

    CAS  PubMed  Google Scholar 

  • Bourne Y, Talley TT, Hansen SB, Taylor P, Marchot P (2005) Crystal structure of a Cbtx-AChBP complex reveals essential interactions between snake alpha-neurotoxins and nicotinic receptors. EMBO J 24(8):1512–1522

    CAS  PubMed Central  PubMed  Google Scholar 

  • Brannigan G, LeBard DN, Hénin J, Eckenhoff RG, Klein ML (2010) Multiple binding sites for the general anesthetic isoflurane identified in the nicotinic acetylcholine receptor transmembrane domain. Proc Natl Acad Sci U S A 107:14122–14127

    CAS  PubMed Central  PubMed  Google Scholar 

  • Brejc K, van Dijk WJ, Klaassen RV, Schuurmans M, van Der OJ, Smit AB, Sixma TK (2001) Crystal structure of an ACh-binding protein reveals the ligand-binding domain of nicotinic receptors. Nature 411(6835):269–276

    CAS  PubMed  Google Scholar 

  • Brown HA (2012) Lipidomics: when apocrypha becomes canonical. Curr Opin Chem Biol 16(1–2):221–226. doi:10.1016/j.cbpa.2012.02.003

    PubMed Central  Google Scholar 

  • Cao L, Young MT, Broomhead HE, Fountain SJ, North RA (2007) Thr339-to-serine substitution in rat P2X2 receptor second transmembrane domain causes constitutive opening and indicates a gating role for Lys308. J Neurosci 27:12916–12923

    CAS  PubMed  Google Scholar 

  • Celie PH, van Rossum-Fikkert SE, van Dijk WJ, Brejc K, Smit AB, Sixma TK (2004) Nicotine and carbamylcholine binding to nicotinic acetylcholine receptors as studied in AChBP crystal structures. Neuron 41(6):907–914

    CAS  PubMed  Google Scholar 

  • Celie PH, Kasheverov IE, Mordvintsev DY, Hogg RC, van Nierop P, van Elk R, van Rossum-Fikkert SE, Zhmak MN, Bertrand D, Tsetlin V, Sixma TK, Smit AB (2005) Crystal structure of nicotinic acetylcholine receptor homolog AChBP in complex with an alpha-conotoxin PnIA variant. Nat Struct Mol Biol 12(7):582–588

    CAS  PubMed  Google Scholar 

  • Changeux JP, Taly A (2008) Nicotinic receptors, allosteric proteins and medicine. Trends Mol Med 14(3):93–102

    CAS  PubMed  Google Scholar 

  • Chen J, Brooks CL 3rd (2007) Can molecular dynamics simulations provide high-resolution refinement of protein structure? Proteins 67(4):922–930

    CAS  PubMed  Google Scholar 

  • Chipot C, Pohorille A (eds) (2007) Free energy calculations: theory and applications in chemistry and biology. Springer, New York

    Google Scholar 

  • Chothia C, Lesk AM (1986) The relation between the divergence of sequence and structure in proteins. EMBO J 5(4):823–826

    CAS  PubMed Central  PubMed  Google Scholar 

  • Conn PJ, Christopoulos A, Lindsley CW (2009) Allosteric modulators of GPCRs: a novel approach for the treatment of CNS disorders. Nat Rev Drug Discov 8(1):41–54. doi:10.1038/nrd2760

    CAS  PubMed Central  PubMed  Google Scholar 

  • Corda D, Di Girolamo M (2003) Functional aspects of protein mono-ADP-ribosylation. EMBO J 22(9):1953–1958

    CAS  PubMed Central  PubMed  Google Scholar 

  • Corringer PJ, Baaden M, Bocquet N, Delarue M, Dufresne V, Nury H, Prevost M, Van Renterghem C (2010) Atomic structure and dynamics of pentameric ligand-gated ion channels: new insight from bacterial homologues. J Physiol 588(4):565–572

    CAS  PubMed Central  PubMed  Google Scholar 

  • Costa V, Nistri A, Cavalli A, Carloni P (2003) A structural model of agonist binding to the alpha3beta4 neuronal nicotinic receptor. Br J Pharmacol 140(5):921–931

    CAS  PubMed Central  PubMed  Google Scholar 

  • Cox K, Bond PJ, Grottesi A, Baaden M, Sansom MSP (2007) Outer membrane proteins: comparing X-Ray and NMR Structures by MD simulations in lipid bilayers. Eur Biophys J 37(2):131–141

    PubMed  Google Scholar 

  • Darve E, Pohorille A (2001) Calculating free energies using average force. J Chem Phys 115:9169–9183

    CAS  Google Scholar 

  • Duret G, Van Renterghem C, Weng Y, Prevost M, Moraga-Cid G, Huon C, Sonner JM, Corringer PJ (2011) Functional prokaryotic-eukaryotic chimera from the pentameric ligand-gated ion channel family. Proc Natl Acad Sci U S A 108:12143–12148

    CAS  PubMed Central  PubMed  Google Scholar 

  • Fan H, Mark AE (2004) Refinement of homology-based protein structures by molecular dynamics simulation techniques. Protein Sci 13(1):211–220

    CAS  PubMed Central  PubMed  Google Scholar 

  • Faraldo-Gomez JD, Forrest LR, Baaden M, Bond PJ, Domene C, Patargias G, Cuthbertson J, Sansom MSP (2004) Conformational sampling and dynamics of membrane proteins from 10-nanosecond computer simulations. Proteins 57(4):783–791

    CAS  PubMed  Google Scholar 

  • Fleming KG, Ackerman AL, Engelman DM (1997) The effect of point mutations on the free energy of transmembrane alpha-helix dimerization. J Mol Biol 272:266–275

    CAS  PubMed  Google Scholar 

  • Gao F, Bern N, Little A, Wang HL, Hansen SB, Talley TT, Taylor P, Sine SM (2003) Curariform antagonists bind in different orientations to acetylcholine-binding protein. J Biol Chem 278(25):23020–23026

    CAS  PubMed Central  PubMed  Google Scholar 

  • Grossfield A (2011) Recent progress in the study of G protein-coupled receptors with molecular dynamics computer simulations. Biochim Biophys Acta 1808(7):1868–1878. doi:10.1016/j.bbamem.2011.03.010

    CAS  PubMed  Google Scholar 

  • Grossfield A, Feller SE, Pitman MC (2007) Convergence of molecular dynamics simulations of membrane proteins. Proteins 67(1):31–40. doi:10.1002/prot.21308

    CAS  PubMed  Google Scholar 

  • Grutter T, Le Novere N, Changeux JP (2004) Rational understanding of nicotinic receptors drug binding. Curr Top Med Chem 4(6):645–650

    CAS  PubMed  Google Scholar 

  • Gumbart J, Chipot C, Schulten K (2011) Free-energy cost for translocon-assisted insertion of membrane proteins. Proc Natl Acad Sci U S A 108:3596–3601

    CAS  PubMed Central  PubMed  Google Scholar 

  • Haddadian EJ, Cheng MH, Coalson RD, Xu Y, Tang P (2008) In silico models for the human alpha4beta2 nicotinic acetylcholine receptor. J Phys Chem B 112(44):13981–13990

    CAS  PubMed Central  PubMed  Google Scholar 

  • Hansen SB, Sulzenbacher G, Huxford T, Marchot P, Taylor P, Bourne Y (2005) Structures of Aplysia AChBP complexes with nicotinic agonists and antagonists reveal distinctive binding interfaces and conformations. EMBO J 24(20):3635–3646

    CAS  PubMed Central  PubMed  Google Scholar 

  • Henchman RH, Wang HL, Sine SM, Taylor P, McCammon JA (2005) Ligand-induced conformational change in the alpha7 nicotinic receptor ligand binding domain. Biophys J 88(4):2564–2576

    CAS  PubMed Central  PubMed  Google Scholar 

  • Hénin J, Chipot C (2004) Overcoming free energy barriers using unconstrained molecular dynamics simulations. J Chem Phys 121:2904–2914

    PubMed  Google Scholar 

  • Hénin J, Pohorille A, Chipot C (2005) Insights into the recognition and association of transmembrane α-helices The free energy of α-helix dimerization in glycophorin A. J Am Chem Soc 127:8478–8484

    PubMed  Google Scholar 

  • Hénin J, Tajkhorshid E, Schulten K, Chipot C (2008) Diffusion of glycerol through Escherichia coli aquaglyceroporin GlpF. Biophys J 94:832–839

    PubMed Central  PubMed  Google Scholar 

  • Hénin J, Fiorin G, Chipot C, Klein ML (2010) Exploring multidimensional free energy landscapes using time-dependent biases on collective variables. J Chem Theory Comput 6:35–47

    Google Scholar 

  • Hilf RJ, Dutzler R (2008) X-ray structure of a prokaryotic pentameric ligand-gated ion channel. Nature 452(7185):375–379

    CAS  PubMed  Google Scholar 

  • Hilf RJ, Dutzler R (2009) Structure of a potentially open state of a proton-activated pentameric ligand-gated ion channel. Nature 457(7225):115–118

    CAS  PubMed  Google Scholar 

  • Hilf RJ, Bertozzi C, Zimmermann I, Reiter A, Trauner D, Dutzler R (2010) Structural basis of open channel block in a prokaryotic pentameric ligand-gated ion channel. Nat Struct Mol Biol 17(11):1330–1336

    CAS  PubMed  Google Scholar 

  • Hinsen K (1998) Analysis of domain motions by approximate normal mode calculations. Proteins 33(3):417–429

    CAS  PubMed  Google Scholar 

  • Hogner A, Kastrup JS, Jin R, Liljefors T, Mayer ML, Egebjerg J, Larsen IK, Gouaux E (2002) Structural basis for AMPA receptor activation and ligand selectivity: crystal structures of five agonist complexes with the GluR2 ligand-binding core. J Mol Biol 322:93

    CAS  PubMed  Google Scholar 

  • Howard RJ, Murail S, Ondricek KE, Corringer PJ, Lindahl E, Trudell JR, Harris RA (2011) Structural basis for alcohol modulation of a pentameric ligand-gated ion channel. Proc Natl Acad Sci U S A 108:12149–12154

    CAS  PubMed Central  PubMed  Google Scholar 

  • Huang X, Zheng F, Stokes C, Papke RL, Zhan CG (2008a) Modeling binding modes of alpha7 nicotinic acetylcholine receptor with ligands: the roles of Gln117 and other residues of the receptor in agonist binding. J Med Chem 51(20):6293–6302

    CAS  Google Scholar 

  • Huang X, Zheng F, Zhan CG (2008b) Modeling differential binding of alpha4beta2 nicotinic acetylcholine receptor with agonists and antagonists. J Am Chem Soc 130(49):16691–16696

    CAS  Google Scholar 

  • Iorga B, Herlem D, Barre E, Guillou C (2006) Acetylcholine nicotinic receptors: finding the putative binding site of allosteric modulators using the “blind docking” approach. J Mol Model 12(3):366–372

    CAS  PubMed  Google Scholar 

  • Ito M, Xu H, Guffanti AA, Wei Y, Zvi L, Clapham DE, Krulwich TA (2004) The voltage-gated Na+ channel NaVBP has a role in motility, chemotaxis, and pH homeostasis of an alkaliphilic Bacillus. Proc Natl Acad Sci U S A 101(29):10566–10571

    CAS  PubMed Central  PubMed  Google Scholar 

  • Ivetac A, Sansom MS (2008) Molecular dynamics simulations and membrane protein structure quality. Eur Biophys J 37(4):403–409

    CAS  PubMed  Google Scholar 

  • Jarzynski C (1997) Nonequilibrium equality for free energy differences. Phys Rev Lett 78:2690–2693

    CAS  Google Scholar 

  • Jensen MØ, Park S, Tajkhorshid E, Schulten K (2002) Energetics of glycerol conduction through aquaglyceroporin GlpF. Proc Natl Acad Sci U S A 99:6731–6736

    CAS  PubMed Central  PubMed  Google Scholar 

  • Jiang LH, Kim M, Spelta V, Bo X, Surprenant A, North RA (2003) Subunit arrangement in P2X receptors. J Neurosci 23:8903

    CAS  PubMed  Google Scholar 

  • Jiang R, Lemoine D, Martz A, Taly A, Gonin S, Prado de Carvalho L, Specht A, Grutter T (2011) Agonist trapped in ATP-binding sites of the P2X2 receptor. Proc Natl Acad Sci U S A 108(22):9066–9071

    CAS  PubMed Central  PubMed  Google Scholar 

  • Jiang R, Taly A, Lemoine D, Martz A, Cunrath O, Grutter T (2012) Tightening of the ATP-binding sites induces the opening of P2X receptor channels. EMBO J 31(9):2134–2143

    CAS  PubMed Central  PubMed  Google Scholar 

  • Jin R, Banke TG, Mayer ML, Traynelis S, Gouaux E (2003) Structural basis for partial agonist action at ionotropic glutamate receptors. Nat Neurosci 6:803

    CAS  PubMed  Google Scholar 

  • Kannan S, Zacharias M (2010) Application of biasing-potential replica-exchange simulations for loop modeling and refinement of proteins in explicit solvent. Proteins 78(13):2809–2819. doi:10.1002/prot.22796

    CAS  PubMed  Google Scholar 

  • Karakas E, Simorowski N, Furukawa H (2009) Structure of the zinc-bound amino-terminal domain of the NMDA receptor NR2B subunit. EMBO J 28(24):3910–3920. doi:10.1038/emboj.2009.338

    CAS  PubMed Central  PubMed  Google Scholar 

  • Kawate T, Michel JC, Birdsong WT, Gouaux E (2009) Crystal structure of the ATP-gated P2X(4) ion channel in the closed state. Nature 460:592

    CAS  PubMed Central  PubMed  Google Scholar 

  • Konstantakaki M, Changeux J, Taly A (2007) Docking of long chain alpha-cobratoxin suggests a basal state conformation of the nicotinic receptor. Biochem Biophys Res Commun 359(3):413–418

    CAS  PubMed  Google Scholar 

  • Krebs WG, Alexandrov V, Wilson CA, Echols N, Yu H, Gerstein M (2002) Normal mode analysis of macromolecular motions in a database framework: developing mode concentration as a useful classifying statistic. Proteins 48(4):682–695

    CAS  PubMed  Google Scholar 

  • Krissinel E, Henrick K. (2004) Secondary-structure matching (SSM), a new tool for fast protein structure alignment in three dimensions. Acta Crystallogr D Biol Crystallogr. 60(Pt 12 Pt 1):2256–68

    Google Scholar 

  • Laurent B, Murail S, Da Silva F, Corringer PJ, Baaden M (2013) Modeling complex biological systems: from solution chemistry to membranes and channels. Pure Appl Chem 85:1–13.

    CAS  Google Scholar 

  • Law RJ, Capener C, Baaden M, Bond PJ, Campbell J, Patargias G, Arinaminpathy Y, Sansom MSP (2005a) Membrane protein structure quality in molecular dynamics simulation. J Mol Graph Model 24(2):157–165

    CAS  Google Scholar 

  • Law RJ, Henchman RH, McCammon JA (2005b) A gating mechanism proposed from a simulation of a human alpha7 nicotinic acetylcholine receptor. Proc Natl Acad Sci U S A 102(19):6813–6818

    CAS  Google Scholar 

  • Le Novere N, Grutter T, Changeux JP (2002) Models of the extracellular domain of the nicotinic receptors and of agonist- and Ca2+-binding sites. Proc Natl Acad Sci U S A 99(5):3210–3215

    CAS  PubMed Central  PubMed  Google Scholar 

  • LeBard DN, Hénin J, Eckenhoff RG, Klein ML, Brannigan G (2012) General anesthetics predicted to block the GLIC Pore with micromolar affinity. PLoS Comput Biol 8:e1002532

    CAS  PubMed Central  PubMed  Google Scholar 

  • Lemoine D, Jiang R, Taly A, Chataigneau T, Specht A, Grutter T (2012) Ligand-gated Ion channels: new insights into neurological disorders and ligand recognition. Chem Rev 112(12):6285–6318

    CAS  PubMed  Google Scholar 

  • Lörinczi É, Bhargava Y, Marino SF, Taly A, Kaczmarek-Hájek K, Barrantes-Freer A, Dutertre S, Grutter T, Rettinger J, Nicke A (2012) Involvement of the cysteine-rich head domain in activation and desensitization of the P2X1 receptor. Proc Natl Acad Sci U S A 109(28):11396–11401

    PubMed Central  PubMed  Google Scholar 

  • Luttmann E, Ludwig J, Hoffle-Maas A, Samochocki M, Maelicke A, Fels G (2009) Structural model for the binding sites of allosterically potentiating ligands on nicotinic acetylcholine receptors. ChemMedChem 4(11):1874–1882

    CAS  PubMed  Google Scholar 

  • MacKenzie KR, Prestegard JH, Engelman DM (1997) A transmembrane helix dimer: structure and implications. Science 276:131–133

    CAS  PubMed  Google Scholar 

  • Mayer ML (2005) Crystal structures of the GluR5 and GluR6 ligand binding cores: molecular mechanisms underlying kainate receptor selectivity. Neuron 45(4):539–552

    CAS  PubMed  Google Scholar 

  • Mayer ML, Ghosal A, Dolman NP, Jane DE (2006) Crystal structures of the kainate receptor GluR5 ligand binding core dimer with novel GluR5-selective antagonists. J Neurosci 26(11):2852–2861

    CAS  PubMed  Google Scholar 

  • Ming D, Wall ME (2005) Allostery in a coarse-grained model of protein dynamics. Phys Rev Lett 95(19):198103

    PubMed  Google Scholar 

  • Mirjalili V, Feig M (2013) Protein structure refinement through structure selection and averaging from molecular dynamics ensembles. J Chem Theory Comput 9(2):1294–1303

    CAS  PubMed Central  PubMed  Google Scholar 

  • Mnatsakanyan N, Jansen M (2013) Experimental determination of the vertical alignment between the second and third transmembrane segments of muscle nicotinic acetylcholine receptors. J Neurochem 125(6):843–854

    CAS  PubMed Central  PubMed  Google Scholar 

  • Nagaya N, Tittle RK, Saar N, Dellal SS, Hume RI (2005) An intersubunit zinc binding site in rat P2X2 receptors. J Biol Chem 280(28):25982–25993

    CAS  PubMed Central  PubMed  Google Scholar 

  • Nicke A, Bäumert HG, Rettinger J, Eichele A, Lambrecht G, Mutschler E, Schmalzing G (1998) P2X1 and P2X3 receptors form stable trimers: a novel structural motif of ligand-gated ion channels. EMBO J 17(11):3016–3028

    CAS  PubMed Central  PubMed  Google Scholar 

  • Nury H, Poitevin F, Van Renterghem C, Changeux JP, Corringer PJ, Delarue M, Baaden M (2010) One-microsecond molecular dynamics simulation of channel gating in a nicotinic receptor homologue. Proc Natl Acad Sci U S A 107:6275–6280

    CAS  PubMed Central  PubMed  Google Scholar 

  • Nury H, Van Renterghem C, Weng Y, Tran A, Baaden M, Dufresne V, Changeux JP, Sonner JM, Delarue M, Corringer PJ (2011) X-ray structures of general anaesthetics bound to a pentameric ligand-gated ion channel. Nature 469(7330):428–431

    CAS  PubMed  Google Scholar 

  • Olivella M, Gonzalez A, Pardo L, Deupi X (2013) Relation between sequence and structure in membrane proteins. Bioinformatics 29(13):1589–1592. doi:10.1093/bioinformatics/btt249

    CAS  PubMed  Google Scholar 

  • Piggot TJ, Holdbrook DA, Khalid S (2013) Conformational dynamics and membrane interactions of the E. coli outer membrane protein FecA: a molecular dynamics simulation study. Biochim Biophys Acta 1828(2):284–293. doi:10.1016/j.bbamem.2012.08.021

    CAS  PubMed  Google Scholar 

  • Prevost M, Sauguet L, Nury H, Van Renterghem C, Huon C, Poitevin F, Baaden M, Delarue M, Corringer PJ (2012) A novel locally closed conformation of a bacterial pentameric proton-gated Ion channel. Nat Struct Mol Biol 19(6):642–649. doi:10.1038/nsmb.2307

    CAS  PubMed  Google Scholar 

  • Raval A, Piana S, Eastwood MP, Dror RO, Shaw DE (2012) Refinement of protein structure homology models via long, all-atom molecular dynamics simulations. Proteins 80(8):2071–2079. doi:10.1002/prot.24098

    CAS  PubMed  Google Scholar 

  • Resat H, Mezei M (1996) Grand canonical ensemble Monte Carlo simulation of the dCpG/proflavine crystal hydrate. Biophys J 71(3):1179–1190

    CAS  PubMed Central  PubMed  Google Scholar 

  • Romo TD, Grossfield A (2011) Block covariance overlap method and convergence in molecular dynamics simulation. J Chem Theory Comput 7(8):2464–2472. doi:10.1021/ct2002754

    CAS  Google Scholar 

  • Šali A (1995) Modelling mutations and homologous proteins. Curr Opin Biotechnol 6(4):437–451

    PubMed  Google Scholar 

  • Samson AO, Levitt M (2008) Inhibition mechanism of the acetylcholine receptor by alpha-neurotoxins as revealed by normal-mode dynamics. Biochemistry 47:4065–4070

    CAS  PubMed Central  PubMed  Google Scholar 

  • Sauguet L, Howard RJ, Malherbe L, Lee US, Corringer PJ, Harris RA, Delarue M (2013a) Structural basis for potentiation by alcohols and anaesthetics in a ligand-gated ion channel. Nat Commun 4:1697. doi:10.1038/ncomms2682

    Google Scholar 

  • Sauguet L, Poitevin F, Murail S, Van Renterghem C, Moraga-Cid G, Malherbe L, Thompson AW, Koehl P, Corringer PJ, Baaden M, Delarue M (2013b) Structural basis for ion permeation mechanism in pentameric ligand-gated ion channels. EMBO J 32(5):728–741. doi:10.1038/emboj.2013.17

    CAS  Google Scholar 

  • Schapira M, Abagyan R, Totrov M (2002) Structural model of nicotinic acetylcholine receptor isotypes bound to acetylcholine and nicotine. BMC Struct Biol 2:1. doi:10.1186/1472-6807-2-1

    PubMed Central  PubMed  Google Scholar 

  • Shevchenko A, Simons K (2010) Lipidomics: coming to grips with lipid diversity. Nat Rev Mol Cell Biol 11(8):593–598. doi:10.1038/nrm2934

    CAS  PubMed  Google Scholar 

  • Shoichet BK, Kobilka BK (2012) Structure-based drug screening for G-protein-coupled receptors. Trends Pharmacol Sci 33(5):268–272

    CAS  PubMed Central  PubMed  Google Scholar 

  • Sine SM (2002) The nicotinic receptor ligand binding domain. J Neurobiol 53(4):431–446

    CAS  PubMed  Google Scholar 

  • Sine SM, Engel AG (2006) Recent advances in Cys-loop receptor structure and function. Nature 440:448–455

    CAS  PubMed  Google Scholar 

  • Sine SM, Wang HL, Gao F (2004) Toward atomic-scale understanding of ligand recognition in the muscle nicotinic receptor. Curr Med Chem 11(5):559–567

    CAS  PubMed  Google Scholar 

  • Sixma TK, Smit AB (2003) Acetylcholine binding protein (AChBP): a secreted glial protein that provides a high-resolution model for the extracellular domain of pentameric ligand-gated ion channels. Annu Rev Biophys Biomol Struct 32:311–334

    CAS  PubMed  Google Scholar 

  • Slavov SH, Radzvilovits M, LeFrancois S, Stoyanova-Slavova IB, Soti F, Kem WR, Katritzky AR (2010) A computational study of the binding of 3-(arylidene) anabaseines to two major brain nicotinic acetylcholine receptors and to the acetylcholine binding protein. Eur J Med Chem 45(6):2433–2446

    CAS  PubMed  Google Scholar 

  • Smit AB, Syed NI, Schaap D, van Minnen J, Klumperman J, Kits KS, Lodder H, van der Schors RC, van Elk R, Sorgedrager B, Brejc K, Sixma TK, Geraerts WP (2001) A glia-derived acetylcholine-binding protein that modulates synaptic transmission. Nature 411(6835):261–268

    CAS  PubMed  Google Scholar 

  • Sobolevsky AI, Rosconi MP, Gouaux E (2009) X-ray structure, symmetry and mechanism of an AMPA-subtype glutamate receptor. Nature 462(7274):745–756

    CAS  PubMed Central  PubMed  Google Scholar 

  • Spurny R, Billen B, Howard RJ, Brams M, Debaveye S, Price KL, Weston DA, Strelkov SV, Tytgat J, Bertrand S, Bertrand D, Lummis SC, Ulens C. (2013) Multisite binding of a general anesthetic to the prokaryotic pentameric Erwinia chrysanthemi ligand-gated ion channel (ELIC). J Biol Chem. 288(12):8355–64

    Google Scholar 

  • Taly A (2007) Opened by a twist: a gating mechanism for the nicotinic acetylcholine receptor. Eur Biophys J 36(8):911–918

    PubMed  Google Scholar 

  • Taly A (2013) Novel approaches to drug design for the treatment of schizophrenia. Expert Opin Drug Discov 8(10):1285–1296. doi:10.1517/17460441.2013.821108

    CAS  PubMed  Google Scholar 

  • Taly A, Changeux JP (2008) Functional organization and conformational dynamics of the nicotinic receptor: a plausible structural interpretation of myasthenic mutations. Ann N Y Acad Sci 1132:42–52

    CAS  PubMed  Google Scholar 

  • Taly A, Delarue M, Grutter T, Nilges M, Le NN, Corringer PJ, Changeux JP (2005) Normal mode analysis suggests a quaternary twist model for the nicotinic receptor gating mechanism. Biophys J 88(6):3954–3965

    CAS  PubMed Central  PubMed  Google Scholar 

  • Taly A, Corringer PJ, Grutter T, Prado deCL, Karplus M, Changeux JP (2006) Implications of the quaternary twist allosteric model for the physiology and pathology of nicotinic acetylcholine receptors. Proc Natl Acad Sci U S A 103(45):16965–16970

    CAS  PubMed Central  PubMed  Google Scholar 

  • Tanner NK, Cordin O, Banroques J, Doère M, Linder P (2003) The Q motif: a newly identified motif in DEAD box helicases may regulate ATP binding and hydrolysis. Mol Cell 11(1):127–138

    CAS  PubMed  Google Scholar 

  • Tasneem A, Iyer LM, Jakobsson E, Aravind L (2005) Identification of the prokaryotic ligand-gated ion channels and their implications for the mechanisms and origins of animal Cys-loop ion channels. Genome Biol 6(1):R4

    PubMed Central  PubMed  Google Scholar 

  • Tirion MM (1996) Large amplitude elastic motions in proteins from a single-parameter, atomic analysis. Phys Rev Lett 77:1905–1908

    CAS  PubMed  Google Scholar 

  • Tittle RK, Hume RI (2008) Opposite effects of zinc on human and rat P2X2 receptors. J Neurosci 28(44):11131–11140

    CAS  PubMed Central  PubMed  Google Scholar 

  • Tittle RK, Power JM, Hume RI (2007) A histidine scan to probe the flexibility of the rat P2X2 receptor zinc-binding site. J Biol Chem 282(27):19526–19533

    CAS  PubMed  Google Scholar 

  • Toshima K, Kanaoka S, Yamada A, Tarumoto K, Akamatsu M, Sattelle DB, Matsuda K (2009) Combined roles of loops C and D in the interactions of a neonicotinoid insecticide imidacloprid with the alpha4beta2 nicotinic acetylcholine receptor. Neuropharmacology 56(1):264–272

    CAS  PubMed  Google Scholar 

  • Turabekova MA, Rasulev BF, Dzhakhangirov FN, Leszczynska D, Leszczynski J (2010) Aconitum and Delphinium alkaloids of curare-like activity. QSAR analysis and molecular docking of alkaloids into AChBP. Eur J Med Chem 45(9):3885–3894

    CAS  PubMed  Google Scholar 

  • Ulens C, Akdemir A, Jongejan A, van Elk R, Edink E, Bertrand S, Perrakis A, Leurs R, Smit AB, Sixma TK, Bertrand D and de Esch IJP (2009) The use of acetylcholine binding protein in the search for novel α7-nicotinic receptor ligands. In silico docking, pharmacological screening and X-ray analysis. J. Med. Chem. 52(8):2372–83

    Google Scholar 

  • Utsintong M, Talley TT, Taylor PW, Olson AJ, Vajragupta O (2009) Virtual screening against alpha-cobratoxin. J Biomol Screen 14(9):1109–1118. doi:10.1177/1087057109344617

    CAS  PubMed Central  PubMed  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(2):112–124. doi:10.1038/nrm2330

    CAS  PubMed Central  PubMed  Google Scholar 

  • Walker JE, Eberle A, Gay NJ, Runswick MJ, Saraste M (1982) Conservation of structure in proton-translocating ATPases of Escherichia coli and mitochondria. EMBO J 10(4):203–206

    CAS  Google Scholar 

  • Weng Y, Yang L, Corringer PJ, Sonner JM (2010) Anesthetic sensitivity of the Gloeobacter violaceus proton-gated ion channel. Anesth Analg 110(1):59–63

    CAS  PubMed Central  PubMed  Google Scholar 

  • Xu Y, Barrantes FJ, Luo X, Chen K, Shen J, Jiang H (2005) Conformational dynamics of the nicotinic acetylcholine receptor channel: a 35-ns molecular dynamics simulation study. J Am Chem Soc 127(4):1291–1299

    CAS  PubMed  Google Scholar 

  • Yi M, Tjong H, Zhou HX (2008) Spontaneous conformational change and toxin binding in alpha7 acetylcholine receptor: insight into channel activation and inhibition. Proc Natl Acad Sci U S A 105(24):8280–8285. doi:10.1073/pnas.0710530105

    CAS  PubMed Central  PubMed  Google Scholar 

  • Zuckerman DM (2010) Statistical physics of biomolecules: an introduction. CRC Press, Salem

    Google Scholar 

  • Zuckerman DM (2011) Equilibrium sampling in biomolecular simulations. Annu Rev Biophys 40:41–62

    CAS  PubMed  Google Scholar 

Download references

Acknowledgments

M.B. thanks the French Agency for Research for funding (Grant ANR-07-CIS7-003-01). This work was supported by the “Initiative d’Excellence” program from the French State (Grant “DYNAMO”, ANR-11-LABX-0011). Benoist Laurent and Samuel Murail are acknowledged for contribution to several figures.

Author information

Authors and Affiliations

  1. Laboratory of Theoretical Biochemistry, Institute of Physico-Chemical Biology, French National Centre for Scientific Research, Université Paris Diderot, 13 rue Pierre et Marie Curie, 75005, Paris, France

    Jérôme Hénin, Marc Baaden & Antoine Taly

Authors
  1. Jérôme Hénin
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Marc Baaden
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Antoine Taly
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Marc Baaden .

Editor information

Editors and Affiliations

  1. UMR-CNRS 7275, Institute of Molecular and Cellular Pharmacology, Valbonne, France

    Isabelle Mus-Veteau

Rights and permissions

Reprints and permissions

Copyright information

© 2014 Springer Science+Business Media New York

About this chapter

Cite this chapter

Hénin, J., Baaden, M., Taly, A. (2014). Foundations of Biomolecular Simulations: A Critical Introduction to Homology Modeling, Molecular Dynamics Simulations, and Free Energy Calculations of Membrane Proteins. In: Mus-Veteau, I. (eds) Membrane Proteins Production for Structural Analysis. Springer, New York, NY. https://doi.org/10.1007/978-1-4939-0662-8_13

Download citation

Publish with us

Policies and ethics

Search

Navigation