Skip to main content
Springer Nature Link
Log in

TMDIM: an improved algorithm for the structure prediction of transmembrane domains of bitopic dimers

  • Published:
Journal of Computer-Aided Molecular Design Aims and scope Submit manuscript

Abstract

\(\alpha\)-Helical transmembrane proteins are the most important drug targets in rational drug development. However, solving the experimental structures of these proteins remains difficult, therefore computational methods to accurately and efficiently predict the structures are in great demand. We present an improved structure prediction method TMDIM based on Park et al. (Proteins 57:577–585, 2004) for predicting bitopic transmembrane protein dimers. Three major algorithmic improvements are introduction of the packing type classification, the multiple-condition decoy filtering, and the cluster-based candidate selection. In a test of predicting nine known bitopic dimers, approximately 78% of our predictions achieved a successful fit (RMSD <2.0 Å) and 78% of the cases are better predicted than the two other methods compared. Our method provides an alternative for modeling TM bitopic dimers of unknown structures for further computational studies. TMDIM is freely available on the web at https://cbbio.cis.umac.mo/TMDIM. Website is implemented in PHP, MySQL and Apache, with all major browsers supported.

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

Access this article

Log in via an institution

Subscribe and save

Springer+ Basic
$34.99 /Month
  • Get 10 units per month
  • Download Article/Chapter or eBook
  • 1 Unit = 1 Article or 1 Chapter
  • Cancel anytime
Subscribe now

Buy Now

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2
Fig. 3
Fig. 4
Fig. 5
Fig. 6

Similar content being viewed by others

References

  1. Bakan A, Meireles LM, Bahar I (2011) ProDy: protein dynamics inferred from theory and experiments. Bioinformatics 11:1575–1577

    Article  Google Scholar 

  2. Bocharov EV, Pustovalova YE, Pavlov KV, Volynsky PE, Goncharuk MV, Ermolyuk YS, Karpunin DV, Schulga AA, Kirpichnikov MP, Efremov RG, Maslennikov IV, Arseniev AS (2007) Unique dimeric structure of BNip3 transmembrane domain suggests membrane permeabilization as a cell death trigger. J Biol Chem 282:16256–16266

    Article  CAS  Google Scholar 

  3. Bocharov EV, Mayzel ML, Volynsky PE, Goncharuk MV, Ermolyuk YS, Schulga AA, Artemenko EO, Efremov RG, Arseniev AS (2008) Spatial structure and pH-dependent conformational diversity of dimeric transmembrane domain of the receptor tyrosine kinase EphA1. J Biol Chem 283:29385–29395

    Article  CAS  Google Scholar 

  4. Bocharov EV, Mineev KS, Volynsky PE, Ermolyuk YS, Tkach EN, Sobol AG, Chupin VV, Kirpichnikov MP, Efremov RG, Arseniev AS (2008) Spatial structure of the dimeric transmembrane domain of the growth factor receptor ErbB2 presumably corresponding to the receptor active state. J Biol Chem 283:6950–6956

    Article  CAS  Google Scholar 

  5. Bocharov EV, Mineev KS, Goncharuk MV, Arseniev AS (2012) Structural and thermodynamic insight into the process of weak dimerization of the ErbB4 transmembrane domain by solution NMR. Biochim Biophys Acta 1818:2158–2170

    Article  CAS  Google Scholar 

  6. Bocharov EV, Lesovoy MD, Goncharuk SA, Goncharuk MV, Hristova K, Arseniev AS (2013) Structure of FGFR3 transmembrane domain dimer: implications for signaling and human pathologies. Structure 21:2087–2093

    Article  CAS  Google Scholar 

  7. Canutescu AA, Shelenkov AA, Dunbrack RL (2003) A graph-theory algorithm for rapid protein side-chain prediction. Protein Sci 12:2001–2014

    Article  CAS  Google Scholar 

  8. Case DA, Cheatham TE III, Darden T, Gohlke H, Luo R, Merz KM Jr, Onufreiv A, Simmerling C, Wang B, Woods RJ (2005) The amber biomolecular simulation programs. J Comp Chem 26:1668–1688

    Article  CAS  Google Scholar 

  9. Doerr A (2009) Membrane protein structures. Nat Methods 6:35–35

    Article  CAS  Google Scholar 

  10. Ducarme P, Thomas A, Brasseur R (2000) The optimisation of the helix/helix interaction of a transmembrane dimer is improved by the IMPALA restraint field. Biochim Biophys Acta 1509:148–154

    Article  CAS  Google Scholar 

  11. Endres N, Das R, Smith A, Arkhipov A, Kovacs E, Huang Y, Pelton J, Shan Y, Shaw D, Wemmer D, Groves J, Kuriyan J (2013) Conformational coupling across the plasma membrane in activation of the EGF receptor. Cell 152:543–556

    Article  CAS  Google Scholar 

  12. 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 321:363–378

    Article  CAS  Google Scholar 

  13. Fuchs A, Martin-Galiano AJ, Kalman M, Fleishman S, Ben-Tal N, Frishman D (2007) Co-evolving residues in membrane proteins. Bioinformatics 23:3312–3319

    Article  CAS  Google Scholar 

  14. Kim S, Chamberlain AK, Bowie JU (2003) A simple method for modeling transmembrane helix oligomers. J Mol Biol 329:831–840

    Article  CAS  Google Scholar 

  15. Kim S, Jeon TJ, Oberai A, Yang D, Schmidt JJ, Bowie JU (2005) Transmembrane glycine zippers: physiological and pathological roles in membrane proteins. Proc Natl Acad Sci USA 102:14278–14283

    Article  CAS  Google Scholar 

  16. Kohlbacher O, Lenhof HP (2000) BALL-rapid software prototyping in computational molecular biology. Bioinformatics 16:815–824

    Article  CAS  Google Scholar 

  17. Krivov GG, Shapovalov MV, Dunbrack RL (2009) Improved prediction of protein side-chain conformations with SCWRL4. Proteins 77:778–795

    Article  CAS  Google Scholar 

  18. Li E, Wimley WC, Hristova K (2012) Transmembrane helix dimerization: beyond the search for sequence motifs. Biochim Biophys Acta 1818:183–193

    Article  CAS  Google Scholar 

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

    Article  CAS  Google Scholar 

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

    Article  CAS  Google Scholar 

  21. Miao Z, Cao Y, Jiang T (2011) RASP: rapid modeling of protein side chain conformations. Bioinformatics 27:3117–3122

    Article  CAS  Google Scholar 

  22. Mineev KS, Khabibullina NF, Lyukmanova EN, Dolgik DA, Kirpichnikov MP, Arseniev AS (2011) Spatial structure and dimermonomer equilibrium of the ErbB3 transmembrane domain in DPC micelles. Biochim Biophys Acta 1808:2081–2088

    Article  CAS  Google Scholar 

  23. Mueller BK, Subramaniam S, Senes A (2014) A frequent, GxxxG-mediated, transmembrane association motif is optimized for the formation of interhelical C\(\alpha\)-H hydrogen bonds. Proc Natl Acad Sci USA 111:E888–95

    Article  CAS  Google Scholar 

  24. Muhle-Goll C, Hoffmann S, Afonin S, Grage SL, Polyansky AA, Windisch D, Zeitler M, Brck J, Ulrich AS (2012) Hydrophobic matching controls the tilt and stability of the dimeric platelet-derived growth factor receptor (PDGFR) \(\beta\) transmembrane segment. J Biol Chem 287:26178–26186

    Article  CAS  Google Scholar 

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

    Article  CAS  Google Scholar 

  26. Park Y, Elsner M, Staritzbichler R, Helms V (2004) Novel scoring function for modeling structures of oligomers of transmembrane \(\alpha\)-helices. Proteins 57:577–585

    Article  CAS  Google Scholar 

  27. Polyansky AA, Volynsky PE, Efremov RG (2011) Structural, dynamic, and functional aspects of helix association in membranes: a computational view. Adv Protein Chem Struct Biol 83:129–161

    Article  CAS  Google Scholar 

  28. Polyansky AA, Volynsky PE, Efremov RG (2012) Multistate organization of transmembrane helical protein dimers governed by the host membrane. J Am Chem Soc 134:14390–14400

    Article  CAS  Google Scholar 

  29. Polyansky AA, Chugunov AO, Volynsky PE, Krylov NA, Nolde DE, Efremov RG (2014) PREDDIMER: a web server for prediction of transmembrane helical dimers. Bioinformatics 30:889–890

    Article  CAS  Google Scholar 

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

    Article  CAS  Google Scholar 

  31. Psachoulia E, Fowler PW, Bond PJ, Sansom MS (2008) Helix-helix interactions in membrane proteins: Coarse-grained simulations of glycophorin A helix dimerization. Biochemistry 47:10503–10512

    Article  CAS  Google Scholar 

  32. Psachoulia E, Marshall DP, Sansom MS (2009) Molecular dynamics simulations of the dimerization of transmembrane \(\alpha\)-helices. Acc Chem Res 43:388–396

    Article  Google Scholar 

  33. R Core Team (2017) R: A Language and Environment for Statistical Computing. R Foundation for Statistical Computing, Vienna, Austria, https://www.R-project.org/

  34. Russ WP, Engelman DM (2000) The GxxxG motif: a framework for transmembrane helix-helix association. J Mol Biol 296:911–919

    Article  CAS  Google Scholar 

  35. Shortle D, Simons KT, Baker D (1998) Clustering of low-energy conformations near the native structures of small proteins. Proc Natl Acad Sci USA 95:11158–11162

    Article  CAS  Google Scholar 

  36. Vereshaga YA, Volynsky PE, Nolde DE, Arseniev AS, Efremov RG (2005) Helix interactions in membranes: lessons from unrestrained monte carlo simulations. J Chem Theory Comput 1:1252–1264

    Article  CAS  Google Scholar 

  37. Wan CK, Han W, Wu YD (2011) Parameterization of PACE force field for membrane environment and simulation of helical peptides and helix-helix association. J Chem Theory Comput 8:300–313

    Article  Google Scholar 

  38. Yıldırım MA, Goh KI, Cusick ME, Barabási AL, Vidal M (2007) Drug-target network. Nat Biotechnol 25:1119–1126

    Article  Google Scholar 

  39. Zhang L, Sodt AJ, Venable RM, Pastor RW, Matthias B (2013) Prediction, refinement, and persistency of transmembrane helix dimers in lipid bilayers using implicit and explicit solvent/lipid representations: Microsecond molecular dynamics simulations of ErbB1/B2 and EphA1. Proteins 81:365–376

    Article  CAS  Google Scholar 

Download references

Acknowledgements

We thank Yungki Park and Volkhard Helms for granting the use of their program for the development of TMDIM. This work was performed in part at the High Performance Computing Cluster which is supported by Information and Communication Technology Office (ICTO) of the University of Macau.

Funding

The funding was provided by University of Macau (Grant Number MYRG2014-00104-FST).

Author information

Authors and Affiliations

  1. Department of Computer and Information Science, Faculty of Science and Technology, University of Macau, Avenida da Universidade, Taipa, Macau, China

    Han Cao, Marcus C. K. Ng, Hio Kuan Tai & Shirley W. I. Siu

  2. Department of Pharmaceutical Life Sciences, Faculty of Pharmacy, Universiti Teknologi MARA Cawangan Selangor, 42300 Bandar Puncak Alam, Selangor, Malaysia

    Siti Azma Jusoh

Authors
  1. Han Cao
    View author publications

    You can also search for this author inPubMed Google Scholar

  2. Marcus C. K. Ng
    View author publications

    You can also search for this author inPubMed Google Scholar

  3. Siti Azma Jusoh
    View author publications

    You can also search for this author inPubMed Google Scholar

  4. Hio Kuan Tai
    View author publications

    You can also search for this author inPubMed Google Scholar

  5. Shirley W. I. Siu
    View author publications

    You can also search for this author inPubMed Google Scholar

Corresponding author

Correspondence to Shirley W. I. Siu.

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Cao, H., Ng, M.C.K., Jusoh, S.A. et al. TMDIM: an improved algorithm for the structure prediction of transmembrane domains of bitopic dimers. J Comput Aided Mol Des 31, 855–865 (2017). https://doi.org/10.1007/s10822-017-0047-0

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s10822-017-0047-0

Keywords