Skip to main content

Critical Review of General Guidelines for Membrane Proteins Model Building and Analysis

  • Protocol
  • First Online:
Membrane Protein Structure Determination

Part of the book series: Methods in Molecular Biology ((MIMB,volume 654))

Abstract

Membrane proteins play major roles in many biological processes such as signalling, transport, etc. They have been shown to be involved in the development of many diseases and have become important drug targets per se. The understanding of their functional properties may be facilitated if a 3D structure is available. However, in the case of membrane proteins, only a few 3D structures have been solved to date. Bioinformatics and molecular modelling approaches are thus powerful alternatives to fill the gap between the sequence and the structure. Here, a review of the most recent approaches is proposed together with guidelines on how to use them. In addition, insofar as important biological processes require conformational changes, we discuss some interesting methods aimed at exploring the dynamic behaviour of proteins in their membrane environment. The paper ends with a brief description of useful approaches for determining oligomerisation or ligand binding sites.

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

Access this chapter

Protocol
USD 49.95
Price excludes VAT (USA)
  • Available as PDF
  • Read on any device
  • Instant download
  • Own it forever
eBook
USD 84.99
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 109.99
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

Institutional subscriptions

References

  1. Teller DC, Okada T, Behnke CA, Palczewski K, Stenkamp RE (2001) Advances in determination of a high-resolution three-dimensional structure of rhodopsin, a model of G-protein-coupled receptors (GPCRs). Biochemistry 40(26):7761–7772

    Article  PubMed  CAS  Google Scholar 

  2. Palczewski K, Kumasaka T, Hori T, Behnke CA, Motoshima H, Fox BA et al (2000) Crystal structure of rhodopsin: a G protein-coupled receptor. Science 289(5480):739–745

    Article  PubMed  CAS  Google Scholar 

  3. Murakami M, Kouyama T (2008) Crystal structure of squid rhodopsin. Nature 453(7193):363–367

    Article  PubMed  CAS  Google Scholar 

  4. Shimamura T, Hiraki K, Takahashi N, Hori T, Ago H, Masuda K et al (2008) Crystal structure of squid rhodopsin with intracellularly extended cytoplasmic region. J Biol Chem 283(26):17753–17756

    Article  PubMed  CAS  Google Scholar 

  5. Park JH, Scheerer P, Hofmann KP, Choe H, Ernst OP (2008) Crystal structure of the ligand-free G-protein-coupled receptor opsin. Nature 454(7201):183–187

    Article  PubMed  CAS  Google Scholar 

  6. Warne T, Serrano-Vega MJ, Baker JG, Moukhametzianov R, Edwards PC, Henderson R et al (2008) Structure of a beta1-adrenergic G-protein-coupled receptor. Nature 454(7203):486–491

    Article  PubMed  CAS  Google Scholar 

  7. Rasmussen SGF, Choi H, Rosenbaum DM, Kobilka TS, Thian FS, Edwards PC et al (2007) Crystal structure of the human beta2 adrenergic G-protein-coupled receptor. Nature 450(7168):383–387

    Article  PubMed  CAS  Google Scholar 

  8. Cherezov V, Rosenbaum DM, Hanson MA, Rasmussen SGF, Thian FS, Kobilka TS et al (2007) High-resolution crystal structure of an engineered human beta2-adrenergic G protein-coupled receptor. Science 318(5854):1258–1265

    Article  PubMed  CAS  Google Scholar 

  9. Hanson MA, Cherezov V, Griffith MT, Roth CB, Jaakola V, Chien EYT et al (2008) A specific cholesterol binding site is established by the 2.8 A structure of the human beta2-adrenergic receptor. Structure 16(6):897–905

    Article  PubMed  CAS  Google Scholar 

  10. Edgar R (2004) MUSCLE: a multiple sequence alignment method with reduced time and space complexity. BMC Bioinformatics 5(1):113

    Article  PubMed  Google Scholar 

  11. Edgar RC (2004) MUSCLE: multiple sequence alignment with high accuracy and high throughput. Nucleic Acids Res 32(5):1792–1797

    Article  PubMed  CAS  Google Scholar 

  12. Mosca R, Schneider TR (2008) RAPIDO: a web server for the alignment of protein structures in the presence of conformational change. Nucleic Acids Res 36(Suppl 2):W42–W46

    Article  PubMed  CAS  Google Scholar 

  13. Lomize MA, Lomize AL, Pogozheva ID, Mosberg HI (2006) OPM: orientations of proteins in membranes database. Bioinformatics 22(5):623–625

    Article  PubMed  CAS  Google Scholar 

  14. Tusnády GE, Dosztányi Z, Simon I (2005) PDB_TM: selection and membrane localization of transmembrane proteins in the protein data bank. Nucleic Acids Res 33(Database issue):D275–D278

    Article  PubMed  Google Scholar 

  15. Tusnády GE, Kalmár L, Simon I (2008) TOPDB: topology data bank of transmembrane proteins. Nucleic Acids Res 36(Database issue):D234–D239

    PubMed  Google Scholar 

  16. Tusnády GE, Kalmár L, Hegyi H, Tompa P, Simon I (2008) TOPDOM: database of domains and motifs with conservative location in transmembrane proteins. Bioinformatics 24(12):1469–1470

    Article  PubMed  Google Scholar 

  17. Tusnády GE, Dosztányi Z, Simon I (2004) Transmembrane proteins in the Protein Data Bank: identification and classification. Bioinformatics 20(17):2964–2972

    Article  PubMed  Google Scholar 

  18. Jayasinghe S, Hristova K, White SH (2001) MPtopo: a database of membrane protein topology. Protein Sci 10(2):455–458

    Article  PubMed  CAS  Google Scholar 

  19. Tusnády GE, Simon I (2001) The HMMTOP transmembrane topology prediction server. Bioinformatics 17(9):849–850

    Article  PubMed  Google Scholar 

  20. Krogh A, Larsson B, von Heijne G, Sonnhammer EL (2001) Predicting transmembrane protein topology with a hidden Markov model: application to complete genomes. J Mol Biol 305(3):567–580

    Article  PubMed  CAS  Google Scholar 

  21. Käll L, Krogh A, Sonnhammer ELL (2005) An HMM posterior decoder for sequence feature prediction that includes homology information. Bioinformatics 21(Suppl 1):i251–i257

    Article  PubMed  Google Scholar 

  22. Ganapathiraju M, Balakrishnan N, Reddy R, Klein-Seetharaman J (2008) Transmembrane helix prediction using amino acid property features and latent semantic analysis. BMC Bioinformatics 9(Suppl 1):S4

    Article  PubMed  Google Scholar 

  23. Jones DT (2007) Improving the accuracy of transmembrane protein topology prediction using evolutionary information. Bioinformatics 23(5):538–544

    Article  PubMed  CAS  Google Scholar 

  24. Lo A, Chiu H, Sung T, Lyu P, Hsu W (2008) Enhanced membrane protein topology prediction using a hierarchical classification method and a new scoring function. J Proteome Res 7(2):487–496

    Article  PubMed  CAS  Google Scholar 

  25. Kitsas IK, Hadjileontiadis LJ, Panas SM (2008) Transmembrane helix prediction in proteins using hydrophobicity properties and higher-order statistics. Comput Biol Med 38(8):867–880

    Article  PubMed  CAS  Google Scholar 

  26. Shen H, Chou JJ (2008) MemBrain: improving the accuracy of predicting transmembrane helices. PLoS One 3(6):e2399

    Article  PubMed  Google Scholar 

  27. Bernsel A, Viklund H, Falk J, Lindahl E, von Heijne G, Elofsson A (2008) Prediction of membrane-protein topology from first principles. Proc Natl Acad Sci U S A 105(20):7177–7181

    Article  PubMed  CAS  Google Scholar 

  28. von Heijne G, Gavel Y (1988) Topogenic signals in integral membrane proteins. Eur J Biochem 174(4):671–678

    Article  Google Scholar 

  29. Kobilka B, Schertler GFX (2008) New G-protein-coupled receptor crystal structures: insights and limitations. Trends Pharmacol Sci 29(2):79–83

    Article  PubMed  CAS  Google Scholar 

  30. Zhang Y, Devries ME, Skolnick J (2006) Structure modeling of all identified G protein-coupled receptors in the human genome. PLoS Comput Biol 2(2):e13

    Article  PubMed  Google Scholar 

  31. Kasho VN, Smirnova IN, Kaback HR (2006) Sequence alignment and homology threading reveals prokaryotic and eukaryotic proteins similar to lactose permease. J Mol Biol 358(4):1060–1070

    Article  PubMed  CAS  Google Scholar 

  32. Etchebest C, Popot J (1997) Packing transmembrane α-helices into bundles: computational vs experimental approaches. In: von Heijne G (ed) Membrane protein assembly. Chapman & Hall, New York, pp 221–250

    Google Scholar 

  33. Herzyk P, Hubbard RE (1998) Combined biophysical and biochemical information confirms arrangement of transmembrane helices visible from the three-dimensional map of frog rhodopsin. J Mol Biol 281(4):741–754

    Article  PubMed  CAS  Google Scholar 

  34. Baldwin JM (1993) The probable arrangement of the helices in G protein-coupled receptors. EMBO J 12(4):1693–1703

    PubMed  CAS  Google Scholar 

  35. Baldwin JM, Schertler GF, Unger VM (1997) An alpha-carbon template for the transmembrane helices in the rhodopsin family of G-protein-coupled receptors. J Mol Biol 272(1):144–164

    Article  PubMed  CAS  Google Scholar 

  36. Elofsson A, von Heijne G (2007) Membrane protein structure: prediction versus reality. Annu Rev Biochem 76:125–140

    Article  PubMed  CAS  Google Scholar 

  37. Dastmalchi S, Church WB, Morris MB (2008) Modelling the structures of G protein-coupled receptors aided by three-dimensional validation. BMC Bioinformatics 9(Suppl 1):S14

    Article  PubMed  Google Scholar 

  38. Trabanino RJ, Hall SE, Vaidehi N, Floriano WB, Kam VWT, Goddard WA (2004) First principles predictions of the structure and function of G-protein-coupled receptors: validation for bovine rhodopsin. Biophys J 86(4):1904–1921

    Article  PubMed  CAS  Google Scholar 

  39. Vaidehi N, Floriano WB, Trabanino R, Hall SE, Freddolino P, Choi EJ et al (2002) Prediction of structure and function of G protein-coupled receptors. Proc Natl Acad Sci U S A 99(20):12622–12627

    Article  PubMed  CAS  Google Scholar 

  40. Park Y, Helms V (2006) Assembly of transmembrane helices of simple polytopic membrane proteins from sequence conservation patterns. Proteins 64(4):895–905

    Article  PubMed  CAS  Google Scholar 

  41. Adamian L, Liang J (2006) Prediction of transmembrane helix orientation in polytopic membrane proteins. BMC Struct Biol 6:13

    Article  PubMed  Google Scholar 

  42. McAllister SR, Floudas CA (2008) Alpha-helical topology prediction and generation of distance restraints in membrane proteins. Biophys J 95(11):5281–5295

    Article  PubMed  CAS  Google Scholar 

  43. Yarov-Yarovoy V, Schonbrun J, Baker D (2006) Multipass membrane protein structure prediction using Rosetta. Proteins Struct Funct Bioinf 62(4):1010–1025

    Article  CAS  Google Scholar 

  44. de Brevern AG, Wong H, Tournamille C, Colin Y, Le Van Kim C, Etchebest C (2005) A structural model of a seven-transmembrane helix receptor: the Duffy antigen/receptor for chemokine (DARC). Biochim Biophys Acta 1724(3):288–306

    Article  PubMed  Google Scholar 

  45. Binkowski TA, Naghibzadeh S, Liang J (2003) CASTp: computed atlas of surface topography of proteins. Nucleic Acids Res 31(13):3352–3355

    Article  PubMed  CAS  Google Scholar 

  46. Hubbard S, Thornton J (1996) Naccess V2.1.1: atomic solvent accessible area calculations. http://www.bioinf.manchester.ac.uk/naccess/

  47. Smart OS, Neduvelil JG, Wang X, Wallace BA, Sansom MS (1996) HOLE: a program for the analysis of the pore dimensions of ion channel structural models. J Mol Graph 14(6):354–360, 376

    Article  PubMed  CAS  Google Scholar 

  48. Kabsch W, Sander C (1983) Dictionary of protein secondary structure: pattern recognition of hydrogen-bonded and geometrical features. Biopolymers 22(12):2577–2637

    Article  PubMed  CAS  Google Scholar 

  49. Heinig M, Frishman D (2004) STRIDE: a web server for secondary structure assignment from known atomic coordinates of proteins. Nucleic Acids Res 32(Web server issue):W500–W502

    Article  PubMed  CAS  Google Scholar 

  50. Lomize AL, Pogozheva ID, Lomize MA, Mosberg HI (2006) Positioning of proteins in membranes: a computational approach. Protein Sci 15(6):1318–1333

    Article  PubMed  CAS  Google Scholar 

  51. Chothia C, Levitt M, Richardson D (1981) Helix to helix packing in proteins. J Mol Biol 145(1):215–250

    Article  PubMed  CAS  Google Scholar 

  52. Fleishman SJ, Ben-Tal N (2002) A novel scoring function for predicting the conformations of tightly packed pairs of transmembrane [alpha]-helices. J Mol Biol 321(2):363–378

    Article  PubMed  CAS  Google Scholar 

  53. Gimpelev M, Forrest LR, Murray D, Honig B (2004) Helical packing patterns in membrane and soluble proteins. Biophys J 87(6):4075–4086

    Article  PubMed  CAS  Google Scholar 

  54. Hildebrand PW, Gunther S, Goede A, Forrest L, Frommel C, Preissner R (2008) Hydrogen-bonding and packing features of membrane proteins: functional implications. Biophys J 94(6):1945–1953

    Article  PubMed  CAS  Google Scholar 

  55. Bansal M, Kumar S, Velavan R (2000) HELANAL: a program to characterize helix geometry in proteins. J Biomol Struct Dyn 17(5):811–819

    Article  PubMed  CAS  Google Scholar 

  56. Kumar S, Bansal M (1996) Structural and sequence characteristics of long alpha helices in globular proteins. Biophys J 71(3):1574–1586

    Article  PubMed  CAS  Google Scholar 

  57. Lee HS, Choi J, Yoon S (2007) QHELIX: a computational tool for the improved measurement of inter-helical angles in proteins. Protein J 26(8):556–561

    Article  PubMed  CAS  Google Scholar 

  58. Debret G, Valadié H, Stadler AM, Etchebest C (2007) New insights of membrane environment effects on MscL channel mechanics from theoretical approaches. Proteins 71(3):1183–1196

    Article  Google Scholar 

  59. Guvench O, MacKerell AD (2008) Comparison of protein force fields for molecular dynamics simulations. Methods Mol Biol 443:63–88

    Article  PubMed  CAS  Google Scholar 

  60. Sonne J, Jensen MO, Hansen FY, Hemmingsen L, Peters GH (2007) Reparameterization of all-atom dipalmitoylphosphatidylcholine lipid parameters enables simulation of fluid bilayers at zero tension. Biophys J 92(12):4157–4167

    Article  PubMed  CAS  Google Scholar 

  61. Davis JE, Warren GL, Patel S (2008) Revised charge equilibration potential for liquid alkanes. J Phys Chem B 112(28):8298–8310

    Article  PubMed  CAS  Google Scholar 

  62. Rosso L, Gould IR (2008) Structure and dynamics of phospholipid bilayers using recently developed general all-atom force fields. J Comput Chem 29(1):24–37

    Article  PubMed  CAS  Google Scholar 

  63. Högberg C, Nikitin AM, Lyubartsev AP (2008) Modification of the CHARMM force field for DMPC lipid bilayer. J Comput Chem 29(14):2359–2369

    Article  PubMed  Google Scholar 

  64. Kitao A, Go N (1999) Investigating protein dynamics in collective coordinate space. Curr Opin Struct Biol 9(2):164–169

    Article  PubMed  CAS  Google Scholar 

  65. Isralewitz B, Gao M, Schulten K (2001) Steered molecular dynamics and mechanical functions of proteins. Curr Opin Struct Biol 11(2):224–230

    Article  PubMed  CAS  Google Scholar 

  66. 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

    Article  PubMed  CAS  Google Scholar 

  67. Sperotto MM, May S, Baumgaertner A (2006) Modelling of proteins in membranes. Chem Phys Lipids 141(1–2):2–29

    Article  PubMed  CAS  Google Scholar 

  68. Feig M (2008) Implicit membrane models for membrane protein simulation. Methods Mol Biol 443:181–196

    Article  PubMed  CAS  Google Scholar 

  69. Ritchie DW (2008) Recent progress and future directions in protein–protein docking. Curr Protein Pept Sci 9(1):1–15

    Article  PubMed  CAS  Google Scholar 

  70. Reggio PH (2006) Computational methods in drug design: modeling G protein-coupled receptor monomers, dimers, and oligomers. AAPS J 8(2):E322–E336

    PubMed  Google Scholar 

  71. Prusis P, Uhlén S, Petrovska R, Lapinsh M, Wikberg JES (2006) Prediction of indirect interactions in proteins. BMC Bioinformatics 7:167

    Article  PubMed  Google Scholar 

  72. Bruschweiler R (1995) Collective protein dynamics and nuclear spin relaxation. J Chem Phys 102(8):3396–3403

    Article  Google Scholar 

  73. Andrusier N, Mashiach E, Nussinov R, Wolfson HJ (2008) Principles of flexible protein–protein docking. Proteins 73(2):271–289

    Article  PubMed  CAS  Google Scholar 

  74. Fernández-Recio J, Totrov M, Abagyan R (2003) ICM–DISCO docking by global energy optimization with fully flexible side-chains. Proteins 52(1):113–117

    Article  PubMed  Google Scholar 

Download references

Author information

Authors and Affiliations

Authors

Corresponding author

Correspondence to Catherine Etchebest .

Editor information

Editors and Affiliations

Rights and permissions

Reprints and permissions

Copyright information

© 2010 Springer Science+Business Media, LLC

About this protocol

Cite this protocol

Etchebest, C., Debret, G. (2010). Critical Review of General Guidelines for Membrane Proteins Model Building and Analysis. In: Lacapère, JJ. (eds) Membrane Protein Structure Determination. Methods in Molecular Biology, vol 654. Humana Press, Totowa, NJ. https://doi.org/10.1007/978-1-60761-762-4_19

Download citation

  • DOI: https://doi.org/10.1007/978-1-60761-762-4_19

  • Published:

  • Publisher Name: Humana Press, Totowa, NJ

  • Print ISBN: 978-1-60761-761-7

  • Online ISBN: 978-1-60761-762-4

  • eBook Packages: Springer Protocols

Publish with us

Policies and ethics