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Protein Structure Prediction pp 325–347Cite as

Modeling Transmembrane Helix Bundles by Restrained MD Simulations

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Part of the book series: Methods in Molecular Biology™ ((MIMB,volume 143))

Abstract

Integral membrane proteins are a major challenge for protein-structure prediction. It is estimated that about a third of genes code for membrane proteins (1), and yet high-resolution structures are known for only a handful of these. Furthermore, technical problems of protein expression and crystallization suggest that an explosive expansion in the number of membrane-protein-structure determinations is still in the future. In this chapter, attention is restricted to the major class of membrane proteins, i.e., those formed by bundles of transmembrane (TM) α-helices. Prediction methods also exist for those membrane proteins (e.g., porins and some bacterial toxins) that are formed by β-barrels (Kay Diederichs, personal communication; also see website: http://loop.biologie.uni-konstanz.de/~kay/om_topo_predict2.html). However, these methods are not applicable to the majority of membrane proteins and so are not discussed here.

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References

  1. Walker, J. E. and Saraste, M. (1996) Membrane protein structure. Curr. Opin. Struct. Biol. 6, 457–459.

    Article  PubMed  CAS  Google Scholar 

  2. Popot, J. L. and Engelman, D. M. (1990) Membrane protein folding and oligomerization: the two-state model. Biochemistry 29, 4031–4037.

    Article  PubMed  CAS  Google Scholar 

  3. Brünger, A. T. (1992) X-PLOR Version 3.1. A System for X-ray Crystallography and NMR, Yale University Press, New Haven, CT.

    Google Scholar 

  4. Chrispeels, M. J. and Agre, P. (1994) Aquaporins: water channels in plant and animal cells. Trends Biochem. Sci. 19, 421–425.

    Article  PubMed  CAS  Google Scholar 

  5. Engel, A., Walz, T., and Agre, P. (1994) The aquaporin family of membrane water channels. Curr. Opin. Struct. Biol. 4, 545–553.

    Article  CAS  Google Scholar 

  6. Jung, J. S., Preston, G. M., Smith, B. L., Guggino, W. B., and Agre, P. (1994) Molecular structure of the water channel through aquaporin CHIP: the hourglass model. J. Biol. Chem. 269, 14,648–14,654.

    PubMed  CAS  Google Scholar 

  7. Preston, G. M., Jung, J. S., Guggino, W. B. and Agre, P. (1994) Membrane topology of aquaporin CHIP: analysis of functional epitope-scanning mutants by vectorial proteolysis. J. Biol. Chem. 269, 1668–1673.

    PubMed  CAS  Google Scholar 

  8. Bai, L., Fushimi, K., Sasaki, S., and Marumo, F. (1996) Structure of aquaporin-2 vasopressin water channel. J. Biol. Chem. 271, 5171–5176.

    Article  PubMed  CAS  Google Scholar 

  9. Walz, T., Hirai, T., Murata, K., Heymann, J. B., Smith, B. L., Agre, P., and Engel, A. (1997) The three-dimensional structure of aquaporin-1. Nature 387, 624–627.

    Article  PubMed  CAS  Google Scholar 

  10. Cheng, A., van Hoek, A. N., Yeager, M., Verkman, A. S. and Mitra, A. K. (1997) Three-dimensional organization of a human water channel. Nature 387, 627–630.

    Article  PubMed  CAS  Google Scholar 

  11. Heymann, J. B., Müller, D. J., Mitsuaoka, K. and Engel, A. (1997) Electron and atomic force microscopy of membrane proteins. Curr. Opin. Struct. Biol. 7, 543–549.

    Article  PubMed  CAS  Google Scholar 

  12. Higgins, D. and Taylor, W. R. (2000) Multiple sequence alignment, in Protein Structure Prediction: Methods and Protocols (Webster, D. M. and Walker, J., eds.), Humana Press, Totowa, NJ, pp. 1; 1–18.

    Chapter  Google Scholar 

  13. Rost, B. and Sander, C. (2000) Third generation of secondary structures, in Protein Structure Prediction: Methods and Protocols (Webster, D. and Walker, J., eds.), Humana Press, Totowa, NJ, pp. 5; 1–24.

    Google Scholar 

  14. Russell, R. B. and Barton, G. K. (1993) The limits of protein secondary structure prediction accuracy from multiple sequence alignment. J. Mol. Biol. 234, 951–957.

    Article  PubMed  CAS  Google Scholar 

  15. Bowie, J. U. (1997) Helix packing in membrane proteins. J. Mol. Biol. 272, 780–789.

    Article  PubMed  CAS  Google Scholar 

  16. Komiya, H., Yeates, T. O., Rees, D. C., Allen, J. P., and Feher, G. (1987) Structure of the reaction centre from Rhodobacter sphaeroides R-26 and 2.4.1: symmetry relations and sequence comparisons. Proc. Natl. Acad. Sci. USA 85, 9012–9016.

    Article  Google Scholar 

  17. Donnelly, D., Overington, J. P., Ruffle, S. V., Nugent, J. H. A., and Blundell, T. L. (1993) Modelling a-helical transmembrane domains: the calculation and use of substitution tables for lipid-facing residues. Protein Sci. 2, 55–70.

    PubMed  CAS  Google Scholar 

  18. Watts, A., Ulrich, A. S., and Middleton, D. A. (1995) Membrane-protein structure: the contribution and potential of novel solid-state NMR approaches. Mol. Memb. Biol. 12, 233–246.

    Article  CAS  Google Scholar 

  19. Smith, S. O., Ascheim, K., and Groesbeek, M. (1996) Magic angle spinning NMR spectroscopy of membrane proteins. Q. Rev. Biophys. 4, 395–449.

    Article  Google Scholar 

  20. Donnelly, D. and Findlay, J. B. C. (1994) Seven-helix receptors: structure and modelling. Curr. Opin. Struct. Biol. 4, 582–589.

    Article  CAS  Google Scholar 

  21. Cabiaux, V., Oberg, K. A., Pancoska, P., Walz, T., Agre, P., and Engel, A. (1997) Secondary structures comparison of aquaporin-1 and bacteriorhodopsin. A Fourier transform infrared spectroscopic study of two-dimensional membrane crystals. Biophys. J. 73, 406–417.

    Article  PubMed  CAS  Google Scholar 

  22. Sansom, M. S. P., Kerr, I. D., Law, R., Davison, L., and Tielman, D. P. (1998) Modelling the packing of transmembrane helices application to aquaporin-1. Biochem. Soc. Transac. 26, 509–515.

    CAS  Google Scholar 

  23. Herzyk, P. and Hubbard, R. E. (1995) Automated-method for modeling 7-helix transmembrane receptors from experimental-data. Biophys. J. 69, 2419–2442.

    Article  PubMed  CAS  Google Scholar 

  24. Son, H. S. and Sansom, M. S. P. (1996) Simulation of packing of transmembrane helices. Biochem. Soc. Trans. 24, 140S.

    Google Scholar 

  25. Baker, E. N. and Hubbard, R. E. (1984) Hydrogen bonding in globular proteins. Prog. Biophys. Mol. Biol. 44, 97–179.

    Article  PubMed  CAS  Google Scholar 

  26. Kirkpatrick, S., Gelatt, C. D., and Vecchi, M. P. (1983) Optimization by simulated annealing. Science 220, 671–680.

    Article  PubMed  CAS  Google Scholar 

  27. Chou, K.-C. and Carlacci, L. (1991) Simulated annealing approach to the study of protein structures. Protein Eng. 4, 661–667.

    Article  PubMed  CAS  Google Scholar 

  28. Nilges, M., Clore, G. M., and Gronenborn, A. M. (1988) Determination of three-dimensional structures of proteins from interproton distance data by dynamical simulated annealing from a random array of atoms. Circumventing problems associated with folding. FEBS Lett. 239, 129–136.

    Article  PubMed  CAS  Google Scholar 

  29. Nilges, M. and Brünger, A. T. (1991) Automated modelling of coiled coils: application to the GCN4 dimerization region. Protein Eng. 4, 649–659.

    Article  PubMed  CAS  Google Scholar 

  30. Nilges, M. and Brünger, A. T. (1993) Successful prediction of the coiled coil geometry of the GCN4 leucine zipper domain by simulated annealing: comparison to the X ray structure. Proteins: Struct. Func. Genet. 15, 133–146.

    Article  CAS  Google Scholar 

  31. Treutlein, H. R., Lemmon, M. A., Engelman, D. M., and Brunger, A. T. (1992) The glycophorin A transmembrane domain dimer: sequence specific propensity for a right handed supercoil of helices. Biochemistry 31, 12,726–12,733.

    Article  PubMed  CAS  Google Scholar 

  32. Adams, P. D., Arkin, I. T., Engelman, D. M., and Brünger, A. T. (1995) Computational searching and mutagenesis suggest a structure for the pentameric transmembrane domain of phospholamban. Nat. Struct. Biol. 2, 154–162.

    Article  PubMed  CAS  Google Scholar 

  33. Kerr, I. D., Sankararamakrishnan, R., Smart, O. S., and Sansom, M. S. P. (1994) Parallel helix bundles and ion channels: molecular modelling via simulated annealing and restrained molecular dynamics. Biophys. J. 67, 1501–1515.

    Article  PubMed  CAS  Google Scholar 

  34. Kerr, I. D., Doak, D. G., Sankararamakrishnan, R., Breed, J., and Sansom, M. S. P. (1996) Molecular modelling of Staphylococcal d-toxin ion channels by restrained molecular dynamics. Protein Eng. 9, 161–171.

    Article  PubMed  CAS  Google Scholar 

  35. Sankararamakrishnan, R., Adcock, C., and Sansom, M. S. P. (1996) The pore domain of the nicotinic acetylcholine receptor: molecular modelling and electrostatics. Biophys. J. 71, 1659–1671.

    Article  PubMed  CAS  Google Scholar 

  36. Sansom, M. S. P., Son, H. S., Sankararamakrishnan, R., Kerr, I. D., and Breed, J. (1995) Seven-helix bundles: molecular modelling via restrained molecular dynamics. Biophys. J. 68, 1295–1310.

    Article  PubMed  CAS  Google Scholar 

  37. Sansom, M. S. P. and Kerr, I. D. (1995) Transbilayer pores formed by β-barrels: molecular modelling of pore structures and properties. Biophys. J. 69, 1334–1343.

    Article  PubMed  CAS  Google Scholar 

  38. Sansom, M. S. P., Sankararamakrishnan, R., and Kerr, I. D. (1995) Modelling membrane proteins using structural restraints. Nat. Struct. Biol. 2, 624–631.

    Article  PubMed  CAS  Google Scholar 

  39. Sansom, M. S. P., Kerr, I. D., Smith, G. R., and Son, H. S. (1997) The influenza A virus M2 channel: a molecular modelling and simulation study. Virology 233, 163–173.

    Article  PubMed  CAS  Google Scholar 

  40. Brooks, B. R., Bruccoleri, R. E., Olafson, B. D., States, D. J., Swaminathan, S., and Karplus, M. (1983) CHARMM: a program for macromolecular energy, minimisation, and dynamics calculations. J. Comp. Chem. 4, 187–217.

    Article  CAS  Google Scholar 

  41. Weiner, S. J., Kollman, P. A., Case, D. A., Singh, U. C., Ghio, C., Alagona, G., Profeta, S., and Weiner, P. (1984) A new force field for molecular mechanical simulation of nucleic acids and proteins. J. Am. Chem. Soc. 106, 765–784.

    Article  CAS  Google Scholar 

  42. Pearlman, D. A., Case, D. A., Caldwell, J. W., Ross, W. S., Cheatham, T. E., Debolt, S., Ferguson, D., Seibel, G., and Kollman, P. (1995) Amber, a package of computer-programs for applying molecular mechanics, normal-mode analysis, molecular-dynamics and free-energy calculations to simulate the structural and energetic properties of molecules. Comp. Phys. Commun. 91, 1–41.

    Article  CAS  Google Scholar 

  43. Berendsen, H. J. C., Postma, J. P. M., van Gunsteren, W. F., DiNola, A., and Haak, J. R. (1984) Molecular dynamics with coupling to an external bath. J. Chem. Phys. 81, 3684–3690.

    Article  CAS  Google Scholar 

  44. Hermans, J., Berendsen, H. J. C., van Gunsteren, W. F., and Postma, J. P. M. (1984) A consistent empirical potential for water-protein interactions. Biopolymers 23, 1513–1518.

    Article  CAS  Google Scholar 

  45. Berendsen, H. J. C., van der Spoel, D., and van Drunen, R. (1995) GROMACS: A message-passing parallel molecular dynamics implementation. Comp. Phys. Commun. 95, 43–56.

    Article  Google Scholar 

  46. Bruccoleri, B. (2000) Ab initio loop modeling and its application to homology modeling, in Protein Structure Prediction: Methods and Protocols (Webster, D. and Walker, J., eds.), Humana Press, Totowa, NJ, pp. 11; 1–18.

    Google Scholar 

  47. Smart, O. S., Goodfellow, J. M., and Wallace, B. A. (1993) The pore dimensions of gramicidin A. Biophys. J. 65, 2455–2460.

    Article  PubMed  CAS  Google Scholar 

  48. Smart, O. S., Breed, J., Smith, G. R., and Sansom, M. S. P. (1997) A novel method for structure-based prediction of ion channel conductance properties. Biophys. J. 72, 1109–1126.

    Article  PubMed  CAS  Google Scholar 

  49. Sansom, M. S. P. (1998) Models and simulations of ion channels and related membrane proteins. Curr. Opin. Struct. Biol. 8, 237–244.

    Article  PubMed  CAS  Google Scholar 

  50. Tieleman, D. P., Marrink, S. J., and Berendsen, H. J. C. (1997) A computer perspective of membranes: molecular dynamics studies of lipid bilayer systems. Biochim. Biophys. Acta 1331, 235–270.

    PubMed  CAS  Google Scholar 

  51. Rost, B., Fariselli, P., and Casadio, R. (1996) Topology prediction for helical transmembrane proteins at 86% accuracy. Protein Sci. 5, 1704–1718.

    Article  PubMed  CAS  Google Scholar 

  52. Shen, L., Bassolino, D., and Stouch, T. (1997) Transmembrane helix structure, dynamics, and interactions: multi-nanosecond molecular dynamics simulations. Biophys. J. 73, 3–20.

    Article  PubMed  CAS  Google Scholar 

  53. Woolf, T. B. (1997) Molecular dynamics of individual α-helices of bacteriorhodopsin in dimyristoyl phosphatidylcholine. I. Structure and dynamics. Biophys. J. 73, 2376–2392.

    Article  PubMed  CAS  Google Scholar 

  54. Henderson, P. J. F. (1993) The 12-transmembrane helix transporters. Curr. Opin. Cell Biol. 5, 708–721.

    Article  PubMed  CAS  Google Scholar 

  55. Jones, D. T., Taylor, W. R., and Thornton, J. M. (1994) A model recognition approach to the prediction of all-helical membrane protein structure and topology. Biochemistry 33, 3038–3049.

    Article  PubMed  CAS  Google Scholar 

  56. Persson, B. and Argos, P. (1994) Prediction of transmembrane segments utilising multiple sequence alignments. J. Mol. Biol. 237, 182–192.

    Article  PubMed  CAS  Google Scholar 

  57. Persson, B. and Argos, P. (1997) Prediction of membrane protein topology utilizing multiple sequence alignments. J. Protein Chem. 16, 453–457.

    Article  PubMed  CAS  Google Scholar 

  58. Rost, B., Casadio, R., Fariselli, P., and Sander, C. (1995) Prediction of helical transmembrane segments at 95% accuracy. Protein Sci. 4, 521–533.

    Article  PubMed  CAS  Google Scholar 

  59. von Heijne, G. V. (1992) Membrane protein structure prediction. Hydrophobicity analysis and the positive inside rule. J. Mol. Biol. 225, 487–494.

    Article  Google Scholar 

  60. Claros, M. G. and von Heijne, G. (1994) Toppred-II—an improved software for membrane-protein structure prediction. Comput. Appl. Biosci. 10, 685–686.

    PubMed  CAS  Google Scholar 

  61. Czerzo, M., Wallin, E., Simon, I., von Heijne, G., and Elofsson, A. (1997) Prediction of transmembrane alpha-helices in prokaryotic membrane proteins: the dense alignment surface method. Protein Eng. 10, 673–676.

    Article  Google Scholar 

  62. Kraulis, P. J. (1991) MOLSCRIPT: a program to produce both detailed and schematic plots of protein structures. J. Appl. Cryst. 24, 946–950.

    Article  Google Scholar 

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Authors and Affiliations

  1. Laboratory of Molecular Biophysics, University of Oxford, Oxford, UK

    Mark S. P. Sansom & Leo Davison

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  1. Mark S. P. Sansom
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  2. Leo Davison
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  1. Southern Cross Molecular, Freshford, Bath, UK

    David M. Webster

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© 2000 Humana Press Inc.

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Sansom, M.S.P., Davison, L. (2000). Modeling Transmembrane Helix Bundles by Restrained MD Simulations. In: Webster, D.M. (eds) Protein Structure Prediction. Methods in Molecular Biology™, vol 143. Humana Press. https://doi.org/10.1385/1-59259-368-2:325

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  • DOI: https://doi.org/10.1385/1-59259-368-2:325

  • Publisher Name: Humana Press

  • Print ISBN: 978-0-89603-637-6

  • Online ISBN: 978-1-59259-368-2

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