Biophys J 68(4): 1295-1310

PMC: PMC1282025

PMID: 7787019

Seven-helix bundles: molecular modeling via restrained molecular dynamics.

M Sansom

H Son

R Sankararamakrishnan

I Kerr

J Breed

Abstract

Simulated annealing via restrained molecular dynamics (SA/MD) has been used to model compact bundles of seven approximately (anti)parallel alpha-helices. Seven such helix bundles occur, e.g., in bacteriorhodopsin, in rhodopsin, and in the channel-forming N-terminal domain of Bacillus thuringiensis delta-endotoxin. Two classes of model are considered: (a) those consisting of seven Ala20 peptide chains; and (b) those containing a single polypeptide chain, made up of seven Ala20 helices linked by GlyN interhelix loops (where N = 5 or 10). Three different starting C alpha templates for SA/MD are used, in which the seven helices are arranged (a) on a left-handed circular template, (b) on a bacteriorhodopsin-like template, or (c) on a zig-zag template. The ensembles of models generated by SA/MD are analyzed in terms of their geometry and energetics, and the most stable structures from each ensemble are examined in greater detail. Structures resembling bacteriorhodopsin and structures resembling delta-endotoxin are both represented among the most stable structures. delta-Endotoxin-like structures arise from both circular and bacteriorhodopsin-like C alpha templates. A third helix-packing mode occurs several times among the stable structures, regardless of the C alpha template and of the presence or absence of interhelix loops. It is characterized by a "4 + 1" core, in which four helices form a distorted left-handed supercoil around a central, buried helix. The remaining two helices pack onto the outside of the core. This packing mode is comparable with that proposed for rhodopsin on the basis of two-dimensional electron crystallographic and sequence analysis studies.

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Selected References

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Baldwin JM. The probable arrangement of the helices in G protein-coupled receptors. EMBO J. 1993 Apr;12(4):1693–1703.[PMC free article] [PubMed] [Google Scholar]
Barlow DJ, Thornton JM. Helix geometry in proteins. J Mol Biol. 1988 Jun 5;201(3):601–619. [PubMed] [Google Scholar]
Barsukov IL, Nolde DE, Lomize AL, Arseniev AS. Three-dimensional structure of proteolytic fragment 163-231 of bacterioopsin determined from nuclear magnetic resonance data in solution. Eur J Biochem. 1992 Jun 15;206(3):665–672. [PubMed] [Google Scholar]
Carlacci L, Chou KC. Energetic approach to the folding of four alpha-helices connected sequentially. Protein Eng. 1990 May;3(6):509–514. [PubMed] [Google Scholar]
Carlacci L, Chou KC. Electrostatic interactions between loops and alpha-helices in four-helix bundle proteins. Protein Eng. 1990 Dec;4(2):225–227. [PubMed] [Google Scholar]
Chothia C. Principles that determine the structure of proteins. Annu Rev Biochem. 1984;53:537–572. [PubMed] [Google Scholar]
Chothia C, Levitt M, Richardson D. Helix to helix packing in proteins. J Mol Biol. 1981 Jan 5;145(1):215–250. [PubMed] [Google Scholar]
Chou KC, Zheng C. Strong electrostatic loop-helix interactions in bundle motif protein structures. Biophys J. 1992 Sep;63(3):682–688.[PMC free article] [PubMed] [Google Scholar]
Chou KC, Carlacci L, Maggiora GM, Parodi LA, Schulz MW. An energy-based approach to packing the 7-helix bundle of bacteriorhodopsin. Protein Sci. 1992 Jun;1(6):810–827.[PMC free article] [PubMed] [Google Scholar]
Chou KC, Maggiora GM, Némethy G, Scheraga HA. Energetics of the structure of the four-alpha-helix bundle in proteins. Proc Natl Acad Sci U S A. 1988 Jun;85(12):4295–4299.[PMC free article] [PubMed] [Google Scholar]
Chou KC, Maggiora GM, Scheraga HA. Role of loop-helix interactions in stabilizing four-helix bundle proteins. Proc Natl Acad Sci U S A. 1992 Aug 15;89(16):7315–7319.[PMC free article] [PubMed] [Google Scholar]
Cronet P, Sander C, Vriend G. Modeling of transmembrane seven helix bundles. Protein Eng. 1993 Jan;6(1):59–64. [PubMed] [Google Scholar]
Donnelly D, Overington JP, Ruffle SV, Nugent JH, Blundell TL. Modeling alpha-helical transmembrane domains: the calculation and use of substitution tables for lipid-facing residues. Protein Sci. 1993 Jan;2(1):55–70.[PMC free article] [PubMed] [Google Scholar]
Edholm O, Jähnig F. The structure of a membrane-spanning polypeptide studied by molecular dynamics. Biophys Chem. 1988 Jul 15;30(3):279–292. [PubMed] [Google Scholar]
Engelman DM, Henderson R, McLachlan AD, Wallace BA. Path of the polypeptide in bacteriorhodopsin. Proc Natl Acad Sci U S A. 1980 Apr;77(4):2023–2027.[PMC free article] [PubMed] [Google Scholar]
Henderson R, Baldwin JM, Ceska TA, Zemlin F, Beckmann E, Downing KH. Model for the structure of bacteriorhodopsin based on high-resolution electron cryo-microscopy. J Mol Biol. 1990 Jun 20;213(4):899–929. [PubMed] [Google Scholar]
Hibert MF, Trumpp-Kallmeyer S, Bruinvels A, Hoflack J. Three-dimensional models of neurotransmitter G-binding protein-coupled receptors. Mol Pharmacol. 1991 Jul;40(1):8–15. [PubMed] [Google Scholar]
Higgins CF. The multidrug resistance P-glycoprotein. Curr Opin Cell Biol. 1993 Aug;5(4):684–687. [PubMed] [Google Scholar]
Hol WG, Halie LM, Sander C. Dipoles of the alpha-helix and beta-sheet: their role in protein folding. Nature. 1981 Dec 10;294(5841):532–536. [PubMed] [Google Scholar]
Jähnig F, Edholm O. Modeling of the structure of bacteriorhodopsin. A molecular dynamics study. J Mol Biol. 1992 Aug 5;226(3):837–850. [PubMed] [Google Scholar]
Jones DT, Taylor WR, Thornton JM. A model recognition approach to the prediction of all-helical membrane protein structure and topology. Biochemistry. 1994 Mar 15;33(10):3038–3049. [PubMed] [Google Scholar]
Kahn TW, Engelman DM. Bacteriorhodopsin can be refolded from two independently stable transmembrane helices and the complementary five-helix fragment. Biochemistry. 1992 Jul 7;31(26):6144–6151. [PubMed] [Google Scholar]
Kerr ID, Sankararamakrishnan R, Smart OS, Sansom MS. Parallel helix bundles and ion channels: molecular modeling via simulated annealing and restrained molecular dynamics. Biophys J. 1994 Oct;67(4):1501–1515.[PMC free article] [PubMed] [Google Scholar]
Kühlbrandt W, Wang DN, Fujiyoshi Y. Atomic model of plant light-harvesting complex by electron crystallography. Nature. 1994 Feb 17;367(6464):614–621. [PubMed] [Google Scholar]
Lemmon MA, Engelman DM. Specificity and promiscuity in membrane helix interactions. Q Rev Biophys. 1994 May;27(2):157–218. [PubMed] [Google Scholar]
Lemmon MA, Treutlein HR, Adams PD, Brünger AT, Engelman DM. A dimerization motif for transmembrane alpha-helices. Nat Struct Biol. 1994 Mar;1(3):157–163. [PubMed] [Google Scholar]
Li JD, Carroll J, Ellar DJ. Crystal structure of insecticidal delta-endotoxin from Bacillus thuringiensis at 2.5 A resolution. Nature. 1991 Oct 31;353(6347):815–821. [PubMed] [Google Scholar]
Livingstone CD, Strange PG, Naylor LH. Molecular modelling of D2-like dopamine receptors. Biochem J. 1992 Oct 1;287(Pt 1):277–282.[PMC free article] [PubMed] [Google Scholar]
Lomize AL, Pervushin KV, Arseniev AS. Spatial structure of (34-65)bacterioopsin polypeptide in SDS micelles determined from nuclear magnetic resonance data. J Biomol NMR. 1992 Jul;2(4):361–372. [PubMed] [Google Scholar]
MaloneyHuss K, Lybrand TP. Three-dimensional structure for the beta 2 adrenergic receptor protein based on computer modeling studies. J Mol Biol. 1992 Jun 5;225(3):859–871. [PubMed] [Google Scholar]
Nilges M, Brünger AT. Automated modeling of coiled coils: application to the GCN4 dimerization region. Protein Eng. 1991 Aug;4(6):649–659. [PubMed] [Google Scholar]
Nilges M, Brünger AT. Successful prediction of the coiled coil geometry of the GCN4 leucine zipper domain by simulated annealing: comparison to the X-ray structure. Proteins. 1993 Feb;15(2):133–146. [PubMed] [Google Scholar]
Persson B, Argos P. Prediction of transmembrane segments in proteins utilising multiple sequence alignments. J Mol Biol. 1994 Mar 25;237(2):182–192. [PubMed] [Google Scholar]
Pervushin KV, Arseniev AS. Three-dimensional structure of (1-36)bacterioopsin in methanol-chloroform mixture and SDS micelles determined by 2D 1H-NMR spectroscopy. FEBS Lett. 1992 Aug 17;308(2):190–196. [PubMed] [Google Scholar]
Popot JL, Engelman DM. Membrane protein folding and oligomerization: the two-stage model. Biochemistry. 1990 May 1;29(17):4031–4037. [PubMed] [Google Scholar]
Reddy BV, Blundell TL. Packing of secondary structural elements in proteins. Analysis and prediction of inter-helix distances. J Mol Biol. 1993 Oct 5;233(3):464–479. [PubMed] [Google Scholar]
Richardson JS, Getzoff ED, Richardson DC. The beta bulge: a common small unit of nonrepetitive protein structure. Proc Natl Acad Sci U S A. 1978 Jun;75(6):2574–2578.[PMC free article] [PubMed] [Google Scholar]
Sansom MS. The biophysics of peptide models of ion channels. Prog Biophys Mol Biol. 1991;55(3):139–235. [PubMed] [Google Scholar]
Sansom MS. Structure and function of channel-forming peptaibols. Q Rev Biophys. 1993 Nov;26(4):365–421. [PubMed] [Google Scholar]
Schertler GF, Villa C, Henderson R. Projection structure of rhodopsin. Nature. 1993 Apr 22;362(6422):770–772. [PubMed] [Google Scholar]
Sibanda BL, Blundell TL, Thornton JM. Conformation of beta-hairpins in protein structures. A systematic classification with applications to modelling by homology, electron density fitting and protein engineering. J Mol Biol. 1989 Apr 20;206(4):759–777. [PubMed] [Google Scholar]
Sylte I, Edvardsen O, Dahl SG. Molecular dynamics of the 5-HT1a receptor and ligands. Protein Eng. 1993 Sep;6(7):691–700. [PubMed] [Google Scholar]
Taylor WR, Jones DT, Green NM. A method for alpha-helical integral membrane protein fold prediction. Proteins. 1994 Mar;18(3):281–294. [PubMed] [Google Scholar]
Treutlein HR, Lemmon MA, Engelman DM, Brünger AT. The glycophorin A transmembrane domain dimer: sequence-specific propensity for a right-handed supercoil of helices. Biochemistry. 1992 Dec 29;31(51):12726–12732. [PubMed] [Google Scholar]
Tuffery P, Etchebest C, Popot JL, Lavery R. Prediction of the positioning of the seven transmembrane alpha-helices of bacteriorhodopsin. A molecular simulation study. J Mol Biol. 1994 Mar 4;236(4):1105–1122. [PubMed] [Google Scholar]
Vlassi M, Steif C, Weber P, Tsernoglou D, Wilson KS, Hinz HJ, Kokkinidis M. Restored heptad pattern continuity does not alter the folding of a four-alpha-helix bundle. Nat Struct Biol. 1994 Oct;1(10):706–716. [PubMed] [Google Scholar]
von Heijne G. Membrane protein structure prediction. Hydrophobicity analysis and the positive-inside rule. J Mol Biol. 1992 May 20;225(2):487–494. [PubMed] [Google Scholar]
Zhang D, Weinstein H. Polarity conserved positions in transmembrane domains of G-protein coupled receptors and bacteriorhodopsin. FEBS Lett. 1994 Jan 10;337(2):207–212. [PubMed] [Google Scholar]

Laboratory of Molecular Biophysics, University of Oxford, United Kingdom.

Abstract