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Replica exchange Monte-Carlo simulations of helix bundle membrane proteins: rotational parameters of helices

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Abstract

We propose a united-residue model of membrane proteins to investigate the structures of helix bundle membrane proteins (HBMPs) using coarse-grained (CG) replica exchange Monte-Carlo (REMC) simulations. To demonstrate the method, it is used to identify the ground state of HBMPs in a CG model, including bacteriorhodopsin (BR), halorhodopsin (HR), and their subdomains. The rotational parameters of transmembrane helices (TMHs) are extracted directly from the simulations, which can be compared with their experimental measurements from site-directed dichroism. In particular, the effects of amphiphilic interaction among the surfaces of TMHs on the rotational angles of helices are discussed. The proposed CG model gives a reasonably good structure prediction of HBMPs, as well as a clear physical picture for the packing, tilting, orientation, and rotation of TMHs. The root mean square deviation (RMSD) in coordinates of Cα atoms of the ground state CG structure from the X-ray structure is 5.03 Å for BR and 6.70 Å for HR. The final structure of HBMPs is obtained from the all-atom molecular dynamics simulations by refining the predicted CG structure, whose RMSD is 4.38 Å for BR and 5.70 Å for HR.

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References

  1. Gerstein M (1998) Patterns of protein-fold usage in fight microbial genomes: a comprehensive structural census. Proteins 33(4):518–534

    Article  CAS  Google Scholar 

  2. Wallin E, von Heijne G (1998) Genome-wide analysis of integral membrane proteins from eubacterial, archaean, and eukaryotic organisms. Protein Sci 7(4):1029–1038

    Article  CAS  Google Scholar 

  3. Krogh A, Larsson B, von Heijne G, Sonnhammer ELL (2001) Predicting transmembrane protein topology with a hidden Markov model: application to complete genomes. J Mol Biol 305(3):567–580. doi:10.1006/jmbi.2000.4315

    Article  CAS  Google Scholar 

  4. White SH, Wimley WC (1999) Membrane protein folding and stability: physical principles. Annu Rev Biophys Biomol Struct 28:319–365

    Article  CAS  Google Scholar 

  5. Drews J (2000) Drug discovery: a historical perspective. Science 287(5460):1960–1964

    Article  CAS  Google Scholar 

  6. Filmore D (2004) It’s a GPCR world. Mod Drug Discov 7:24–26

    CAS  Google Scholar 

  7. Bowie JU (2005) Solving the membrane protein folding problem. Nature 438(7068):581–589. doi:10.1038/nature04395

    Article  CAS  Google Scholar 

  8. Milik M, Skolnick J (1992) Spontaneous insertion of polypeptide-chains into membranes—a Monte-Carlo model. Proc Natl Acad Sci USA 89(20):9391–9395

    Article  CAS  Google Scholar 

  9. Chen CM (2001) Lattice model of transmembrane polypeptide folding. Phys Rev E 63(1):010901. doi:10.1103/PhysRevE.63.010901

    Google Scholar 

  10. Floriano WB, Vaidehi N, Goddard WA, Singer MS, Shepherd GM (2000) Molecular mechanisms underlying differential odor responses of a mouse olfactory receptor. Proc Natl Acad Sci USA 97(20):10712–10716

    Article  CAS  Google Scholar 

  11. Dobbs H, Orlandini E, Bonaccini R, Seno F (2002) Optimal potentials for predicting inter-helical packing in transmembrane proteins. Proteins 49(3):342–349. doi:10.1002/prot.10229

    Article  CAS  Google Scholar 

  12. Chen CM, Chen CC (2003) Computer Simulations of membrane protein folding: structure and dynamics. Biophys J 84(3):1902–1908

    Article  CAS  Google Scholar 

  13. Kokubo H, Okamoto Y (2004) Self-assembly of transmembrane helices of bacteriorhodopsin by a replica-exchange Monte Carlo simulation. Chem Phys Lett 392(1–3):168–175. doi:10.1016/j.cplett.2004.04.112

    Article  CAS  Google Scholar 

  14. Chen CC, Chen CM (2009) A dual-scale approach toward structure prediction of retinal proteins. J Struct Biol 165(1):37–46. doi:10.1016/j.jsb.2008.10.001

    Article  CAS  Google Scholar 

  15. Chen CC, Wei CC, Sun YC, Chen CM (2008) Packing of transmembrane helices in bacteriorhodopsin folding: structure and thermodynamics. J Struct Biol 162(2):237–247. doi:10.1016/j.jsb.2008.01.003

    Article  CAS  Google Scholar 

  16. Popot JL, Engelman DM (1990) Membrane protein folding and oligomerization: the two-stage model. Biochemistry 29(17):4031–4037

    Article  CAS  Google Scholar 

  17. Popot JL, Engelman DM (2000) Helical membrane protein folding, stability, and evolution. Annu Rev Biochem 69:881–922

    Article  CAS  Google Scholar 

  18. Booth P, Curran A (1999) Membrane protein folding. Curr Opin Struct Biol 9(1):115–121

    Article  CAS  Google Scholar 

  19. Pappu RV, Marshall GR, Ponder JW (1999) A potential smoothing algorithm accurately predicts transmembrane helix packing. Nat Struct Biol 6(1):50–55

    Article  CAS  Google Scholar 

  20. Rees D, DeAntonio L, Eisenberg D (1989) Hydrophobic organization of membrane proteins. Science 245(4917):510–513

    Article  CAS  Google Scholar 

  21. Ulmschneider MB, Sansom MSP, Di Nola A (2005) Properties of integral membrane protein structures: derivation of an implicit membrane potential. Proteins 59(2):252–265. doi:10.1002/prot.20334

    Article  CAS  Google Scholar 

  22. Pilpel Y, Ben-Tal N, Lancet D (1999) kPROT: a knowledge-based scale for the propensity of residue orientation in transmembrane segments. Application to membrane protein structure prediction. J Mol Biol 294(4):921–935. doi:10.1006/jmbi.1999.3257

    Article  CAS  Google Scholar 

  23. Adamian L, Nanda V, DeGrado WF, Liang J (2005) Empirical lipid propensities of amino acid residues in multispan alpha helical membrane proteins. Proteins 59(3):496–509. doi:10.1002/prot.20456

    Article  CAS  Google Scholar 

  24. Adamian L, Liang J (2001) Helix–helix packing and interfacial pairwise interactions of residues in membrane proteins. J Mol Biol 311(4):891–907. doi:10.1006/jmbi.2001.4908

    Article  CAS  Google Scholar 

  25. Choma C, Gratkowski H, Lear JD, DeGrado WF (2000) Asparagine-mediated self-association of a model transmembrane helix. Nat Struct Biol 7(2):161–166. doi:10.1038/72440

    Article  CAS  Google Scholar 

  26. Gratkowski H, Lear JD, DeGrado WF (2001) Polar side chains drive the association of model transmembrane peptides. Proc Natl Acad Sci USA 98(3):880–885. doi:10.1073/pnas.98.3.880

    Article  CAS  Google Scholar 

  27. Yarov-Yarovoy V, Schonbrun J, Baker D (2006) Multipass membrane protein structure prediction using Rosetta. Proteins 62(4):1010–1025. doi:10.1002/prot.20817

    Article  CAS  Google Scholar 

  28. Stevens TJ, Arkin IT (1999) Are membrane proteins “inside–out” proteins? Proteins 36(1):135–143. doi:10.1002/(SICI)1097-0134(19990701)36:1<135::AID-PROT11>3.0.CO;2-I

  29. Barth P (2010) Prediction of three-dimensional transmembrane helical protein structures. In: Frishman D (ed) Structural bioinformatics of membrane proteins. SpringerWienNewYork, New York

    Google Scholar 

  30. Lee J, Wu S, Zhang Y (2009) Ab initio protein structure prediction. In: Rigden DJ (ed) From protein structure to function with bioinformatics. Springer, New York

    Google Scholar 

  31. Trabanino RJ, Hall SE, Vaidehi N, Floriano WB, Kam VW, Goddard WA III (2004) First principles predictions of the structure and function of G-protein-coupled receptors: validation for bovine rhodopsin. Biophys J 86(4):1904–1921. doi:10.1016/S0006-3495(04)74256-3

    Google Scholar 

  32. Arkin IT, MacKenzie KR, Brunger AT (1997) Site-directed dichroism as a method for obtaining rotational and orientational constraints for oriented polymers. J Am Chem Soc 119(38):8973–8980

    Article  CAS  Google Scholar 

  33. Zheng L, Herzfeld J (1992) NMR studies of retinal proteins. J Bioenerg Biomembr 24(2):139–146

    Article  CAS  Google Scholar 

  34. Hansmann UHE (1997) Parallel tempering algorithm for conformational studies of biological molecules. Chem Phys Lett 281:140–150

    Article  CAS  Google Scholar 

  35. Case DA, Cheatham TE III, Darden T, Gohlke H, Luo R, Merz KM Jr, Onufriev A, Simmerling C, Wang B, Woods RJ (2005) The Amber biomolecular simulation programs. J Comput Chem 26(16):1668–1688. doi:10.1002/jcc.20290

    Article  CAS  Google Scholar 

  36. Nolting B (2005) Protein folding kinetics: biophysical methods. Springer, New York

    Google Scholar 

  37. Kyte J, Doolittle RF (1982) A simple method for displaying the hydropathic character of a protein. J Mol Biol 157(1):105–132. doi:10.1016/0022-2836(82)90515-0

    Google Scholar 

  38. Rose GD, Wolfenden R (1993) Hydrogen bonding, hydrophobicity, packing, and protein folding. Annu Rev Biophys Biomol Struct 22:381–415. doi:10.1146/annurev.bb.22.060193.002121

    Article  CAS  Google Scholar 

  39. Huschilt J, Hodges R, Davis J (1985) Phase equilibria in an amphiphilic peptide-phospholipid model membrane by deuterium nuclear magnetic resonance difference spectroscopy. Biochemistry 24(6):10

    Article  Google Scholar 

  40. Subczynski WK, Lewis RN, McElhaney RN, Hodges RS, Hyde JS, Kusumi A (1998) Molecular organization and dynamics of 1-palmitoyl-2-oleoylphosphatidylcholine bilayers containing a transmembrane alpha-helical peptide. Biochemistry 37(9):3156–3164. doi:10.1021/bi972148+

    Google Scholar 

  41. May S, Ben-Shaul A (1999) Molecular theory of lipid-protein interaction and the l-alpha-H-II transition. Biophys J 76(2):751–767

    Article  CAS  Google Scholar 

  42. McLean LR, Hagaman KA, Owen TJ, Krstenansky JL (1991) Minimal peptide length for interaction of amphipathic alpha-helical peptides with phosphatidylcholine liposomes. Biochemistry 30(1):31–37

    Article  CAS  Google Scholar 

  43. Kiyota T, Lee S, Sugihara G (1996) Design and synthesis of amphiphilic alpha-helical model peptides with systematically varied hydrophobic-hydrophilic balance and their interaction with lipid- and bio-membranes. Biochemistry 35(40):13196–13204. doi:10.1021/bi961289t

    Google Scholar 

  44. For simplicity, the HI vector of AFs only contains 5 elements. For an AF with 6 residues, its HI vector would be simplified to be <(HI1+HI2) ×0.5, (HI2+HI3) ×0.5, (HI3+HI4) ×0.5, (HI4+HI5) ×0.5, (HI5+HI6) ×0.5>

  45. There are three conditions for the j1-th AF of helix i1 and the j2-th AF of helix i2 to have proper contact: (1) the distance between these two helices is less than 30 Å, (2) there is no other helix in between them, and (3) the distance between j1-th AF and j2-th AF are the shortest in all 16 AF pairs between these two helices

  46. Nina M, Roux B, Smith JC (1995) Functional interactions in bacteriorhodopsin: a theoretical analysis of retinal hydrogen bonding with water. Biophys J 68(1):25–39. doi:10.1016/S0006-3495(95)80184-0

    Google Scholar 

  47. Baudry J, Crouzy S, Roux B, Smith JC (1999) Simulation analysis of the retinal conformational equilibrium in dark-adapted bacteriorhodopsin. Biophys J 76(4):1909–1917

    Article  CAS  Google Scholar 

  48. Swendsen RH, Wang JS (1986) Replica Monte Carlo simulation of spin glasses. Phys Rev Lett 57(21):2607–2609

    Article  Google Scholar 

  49. Kofke DA (2002) On the acceptance probability of replica-exchange Monte Carlo trials. J Chem Phys 117(15):6911–6914. doi:10.1063/11507776

    Article  CAS  Google Scholar 

  50. Tajkhorshid E, Paizs B, Suhai S (1999) Role of isomerization barriers in the pK(a) control of the retinal Schiff base: a density functional study. J Phys Chem B 103(21):4518–4527

    Article  CAS  Google Scholar 

  51. Tsong TY (1990) Electrical modulation of membrane proteins: enforced conformational oscillations and biological energy and signal transductions. Annu Rev Biophys Biophys Chem 19:83–106. doi:10.1146/annurev.bb.19.060190.000503

    Article  CAS  Google Scholar 

  52. Anfinsen CB (1973) Principles that govern the folding of protein chains. Science 181(96):223–230

    Article  CAS  Google Scholar 

  53. Huang KS, Bayley H, Liao MJ, London E, Khorana HG (1981) Refolding of an integral membrane protein. Denaturation, renaturation, and reconstitution of intact bacteriorhodopsin and two proteolytic fragments. J Biol Chem 256(8):3802–3809

    CAS  Google Scholar 

  54. London E, Khorana HG (1982) Denaturation and renaturation of bacteriorhodopsin in detergents and lipid-detergent mixtures. J Biol Chem 257(12):7003–7011

    CAS  Google Scholar 

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Acknowledgments

This work is supported by the National Science Council of Taiwan under grant of no. NSC 97-2112-M-003-005-MY2.

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  1. Department of Physics, National Taiwan Normal University, 88 Sec. 4 Ting-Chou Rd., Taipei, 116, Taiwan

    H.-H. Wu, C.-C. Chen & C.-M. Chen

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  1. H.-H. Wu
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Correspondence to C.-M. Chen.

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Wu, HH., Chen, CC. & Chen, CM. Replica exchange Monte-Carlo simulations of helix bundle membrane proteins: rotational parameters of helices. J Comput Aided Mol Des 26, 363–374 (2012). https://doi.org/10.1007/s10822-012-9562-1

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