Journal of Molecular Modeling

, Volume 17, Issue 2, pp 401–413

Analysis of structural water and CH···π interactions in HIV-1 protease and PTP1B complexes using a hydrogen bond prediction tool, HBPredicT

  • Joshy P. Yesudas
  • Fareed Bhasha Sayyed
  • Cherumuttathu H. Suresh
Original Paper


A hydrogen bond prediction tool HBPredicT is developed for detecting structural water molecules and CH···π interactions in PDB files of protein-ligand complexes. The program adds the missing hydrogen atoms to the protein, ligands, and oxygen atoms of water molecules and subsequently all the hydrogen bonds in the complex are located using specific geometrical criteria. Hydrogen bonds are classified into various types based on (i) donor and acceptor atoms, and interactions such as (ii) protein-protein, (iii) protein-ligand, (iv) protein-water, (v) ligand-water, (vi) water-water, and (vii) protein-water-ligand. Using the information in category (vii), the water molecules which form hydrogen bonds with the ligand and the protein simultaneously–the structural water–is identified and retrieved along with the associated ligand and protein residues. For CH···π interactions, the relevant portions of the corresponding structures are also extracted in the output. The application potential of this program is tested using 19 HIV-1 protease and 11 PTP1B inhibitor complexes. All the systems showed presence of structural water molecules and in several cases, the CH···π interaction between ligand and protein are detected. A rare occurrence of CH···π interactions emanating from both faces of a phenyl ring of the inhibitor is identified in HIV-1 protease 1D4L.


Concurrent two CH···π interactions of an aromatic ring in the HIV-protease system 1D4L, located using HBPredicT


CH···π interactions HIV protease Hydrogen bond Protein-ligand interactions PTP1B Structural water 

Supplementary material

894_2010_736_MOESM1_ESM.pdf (38 kb)
ESM 1(PDF 37 kb)


  1. 1.
    Jackson RC (1997) Contributions of protein structure-based drug design to cancer chemotherapy. Semin Oncol 24:164–172Google Scholar
  2. 2.
    Parlow JJ, Case BL, Dice TA, Fenton RL, Hayes MJ, Jones DE, Neumann WL, Wood RS, Lachance RM, Girard TJ, Nicholson NS, Clare M, Stegeman RA, Stevens AM, Stallings WC, Kurmbail RG, South MS (2003) Design, parallel synthesis, and crystal structures of pyrazinone antithrombotics as selective inhibitors of the tissue factor VIIa complex. J Med Chem 46:4050–4062CrossRefGoogle Scholar
  3. 3.
    Rowland RS (2002) Using X-ray crystallography in drug discovery. Curr Opin Drug Discov Develop 5:613–619Google Scholar
  4. 4.
    Terasaka T, Kinoshita T, Kuno M, Seki N, Tanaka K, Nakanishi I (2004) Structure-based design, synthesis, and structure-activity relationship studies of novel non-nucleoside adenosine deaminase inhibitors. J Med Chem 47:3730–3743CrossRefGoogle Scholar
  5. 5.
    Blundell TL (1996) Structure-based drug design. Nature 384S:23–26Google Scholar
  6. 6.
    Kellogg GE, Abraham DJ (2000) Hydrophobicity: is LogP(o/w) more than the sum of its parts? Eur J Med Chem 35:651–661CrossRefGoogle Scholar
  7. 7.
    Nishio M, Umezawa Y, Hirota M, Takeuchi Y (1995) The CH/π interaction: significance in molecular recognition. Tetrahedron 51:8665–8701CrossRefGoogle Scholar
  8. 8.
    Jeffrey GA, Saenger W (1991) Hydrogen bonding in biological structures. Springer, BerlinGoogle Scholar
  9. 9.
    Poornima CS, Dean PM (1995) Hydration in drug design. 1. Multiple hydrogen-bonding features of water molecules in mediating protein-ligand interactions. J Comput Aided Mol Des 9:500–512CrossRefGoogle Scholar
  10. 10.
    Fornabaio M, Spyrakis F, Mozzarelli A, Cozzini P, Abraham DJ, Kellogg GE (2004) Simple, intuitive calculations of free energy of binding for protein-ligand complexes. 3. The free energy contribution of structural water molecules in HIV-1 protease complexes. J Med Chem 47:4507–4516CrossRefGoogle Scholar
  11. 11.
    Ladbury JE (1996) Just add water! The effect of water on the specificity of protein-ligand binding sites and its potential application to drug design. Chem Biol 3:973–980CrossRefGoogle Scholar
  12. 12.
    Connelly PR (1994) Acquisition and use of calorimetric data for prediction of the thermodynamics of ligand-binding and folding reactions of proteins. Curr Opin Biotechnol 5:381–388CrossRefGoogle Scholar
  13. 13.
    Suresh CH, Vargheese AM, Vijayalakshmi P, Neetha M, Koga N (2008) Role of structural water molecule in HIV protease-inhibitor complexes: a QM/MM study. J Comput Chem 29:1840–1849CrossRefGoogle Scholar
  14. 14.
    Fischer S, Verma CS (1999) Binding of buried structural water increases the flexibility of proteins. Proc Natl Acad Sci U S A 96:9613–9615CrossRefGoogle Scholar
  15. 15.
    Nishio M, Umezawa Y, Honda K, Tsuboyama S, Suezawa H (2009) CH/π hydrogen bonds in organic and organometallic chemistry. Cryst Eng Comm 11:1757–1788Google Scholar
  16. 16.
    Ozawa T, Tsuji E, Ozawa M, Handa C, Mukaiyama H, Nishimura T, Kobayashi S, Okazaki K (2008) The importance of CH/π hydrogen bonds in rational drug design: an ab initio fragment molecular orbital study to leukocyte-specific protein tyrosine (LCK) kinase. Bioorg Med Chem 24:10311–10318CrossRefGoogle Scholar
  17. 17.
    Harigai M, Kataoka M, Imamoto Y (2006) A single CH/π weak hydrogen bond governs stability and the photocycle of the photoactive yellow protein. J Am Chem Soc 128:10646–10647CrossRefGoogle Scholar
  18. 18.
    Muraki M (2002) The importance of CH/π interactions to the function of carbohydrate binding proteins. Protein Pept Lett 9:195–209CrossRefGoogle Scholar
  19. 19.
    Huber RE, Hakda S, Cheng C, Cupples CG, Edwards RA (2003) Trp-999 of β-galactosidase (Escherichia coli) is a key residue for binding, catalysis, and synthesis of allolactose, the natural Lac operon inducer. Biochemistry 42:1796–1803CrossRefGoogle Scholar
  20. 20.
    Poole DM, Hazlewood GP, Huskisson NS, Virden R, Gilbert HJ (1993) The role of conserved tryptophan residues in the interaction of a bacterial cellulose binding domain with its ligand. FEMS Microbiol Lett 106:77–84CrossRefGoogle Scholar
  21. 21.
    Davis R, Saleesh Kumar NS, Abraham S, Suresh CH, Rath NP, Tamaoki N, Das S (2008) Molecular packing and solid-state fluorescence of alkoxy-cyano substituted diphenylbutadienes: structure of the luminescent aggregates. J Phys Chem C 112:2137–2146CrossRefGoogle Scholar
  22. 22.
    Radhakrishnan KV, Anas S, Suresh E, Koga N, Suresh CH (2007) Molecular recognition in an organic host-guest complex: CH⋯O and CH⋯π interactions completely control the crystal packing and the host-guest complexation. Bull Chem Soc Jpn 80:484–490CrossRefGoogle Scholar
  23. 23.
    Spiwok V, Lipovova P, Skalova T, Buchtelova E, Hasek J, Kralova B (2004) Role of CH/π interactions in substrate binding by Escherichia coli β-galactosidase. Carbohydr Res 339:2275–2280CrossRefGoogle Scholar
  24. 24.
    Chakrabarti P, Samanta U (1995) CH/π interaction in the packing of the adenine ring in protein structures. J Mol Biol 251:9–14CrossRefGoogle Scholar
  25. 25.
    Umezawa Y, Nishio M (2005) CH/π hydrogen bonds as evidenced in the substrate specificity of acetylcholine esterase. Biopolymers 79:248–258CrossRefGoogle Scholar
  26. 26.
    Humphrey W, Dalke A, Schulten K (1996) VMD: visual molecular dynamics. J Mol Graphics 14:33–38CrossRefGoogle Scholar
  27. 27.
    Guex N, Peitsch MC (1997) SWISS-MODEL and the Swiss-PdbViewer: An environment for comparative protein modeling. Electrophoresis 18:2714–2723CrossRefGoogle Scholar
  28. 28.
    Word JM, Lovell SC, Richardson JS, Richardson DC (1999) Asparagine and glutamine: using hydrogen atom contacts in the choice of side-chain amide orientation. J Mol Biol 285:1735–1747CrossRefGoogle Scholar
  29. 29.
    Tiwari A, Panigrahi SK (2007) HBAT: a complete package for analysing strong and weak hydrogen bonds in macromolecular crystal structures. In Silico Biol 7:651–661Google Scholar
  30. 30.
    Lindauer K, Bendic C, Sühnel J (1996) HBexplore-a new tool for identifying and analysing hydrogen bonding patterns in biological macromolecules. Comput Appl Biosci 12:281–289Google Scholar
  31. 31.
    McDonald IK, Thornton JM (1994) Satisfying hydrogen bonding potential in proteins. J Mol Biol 238:777–793CrossRefGoogle Scholar
  32. 32.
    Kaur H, Raghava GPS (2006) Prediction of Cα-H⋯O and Cα-H⋯π interactions in proteins using recurrent neural network. In Silico Biol 6:111–125Google Scholar
  33. 33.
    Evans JL, Jallal B (1999) Protein tyrosine phosphatases: Their role in insulin action and potential as drug targets. Exp Opin Invest Drugs 8:139–160CrossRefGoogle Scholar
  34. 34.
    Hashimoto N, Zhang WR, Goldstein BJ (1992) Insulin receptor and epidermal growth factor receptor dephosphorylation by three major rat liver protein-tyrosine phosphatases expressed in a recombinant bacterial system. Biochem J 284:569–576Google Scholar
  35. 35.
    Berman HM, Westbrook J, Feng Z, Gilliland G, Bhat TN, Weissig H, Shindyalov IN, Bourne PE (2000) The protein data bank. Nucleic Acids Res 28:235–242CrossRefGoogle Scholar
  36. 36.
    Sayle RA, Milner-White E (1995) RASMOL: Biomolecular graphics for all. J Trends Biochem Sci 20:374–376CrossRefGoogle Scholar
  37. 37.
    Budayova-Spano M, Fisher SZ, Dauvergne M, Agbandje-McKenna M, Silverman DN, Myles DAA, McKenna R (2006) Production and X-ray crystallographic analysis of fully deuterated human carbonic anhydrase II. Acta Crystallogr F 62:6–9CrossRefGoogle Scholar
  38. 38.
    Baker EN, Hubbard RE (1984) Hydrogen bonding in globular proteins. Prog Biophys Mol Biol 44:97–179CrossRefGoogle Scholar
  39. 39.
    Desiraju GR (2002) Hydrogen bridges in crystal engineering: Interactions without borders. Acc Chem Res 35:565–573CrossRefGoogle Scholar
  40. 40.
    Desiraju GR (1991) The C-H-O hydrogen bond in crystals: What is it? Acc Chem Res 24:290–296CrossRefGoogle Scholar
  41. 41.
    Brandl M, Weiss MS, Jabs A, Sühnel J, Hilgenfeld R (2001) C-H···π-interactions in proteins. J Mol Biol 307:357–377CrossRefGoogle Scholar
  42. 42.
    Hosur MV, Bhat TN, Kempf D, Baldwin ET, Liu B, Gulnik S, Wideburg NE, Norbeck DW, Appelt K, Erickson JW (1994) Influence of stereochemistry on activity and binding modes for C2 symmetry-based diol inhibitors of HIV-1 protease. J Am Chem Soc 116:847–855CrossRefGoogle Scholar
  43. 43.
    Tyndall JDA, Reid RC, Tyssen DP, Jardine DK, Todd B, Passmore M, March DR, Pattenden LK, Bergman DA, Alewood D, Hu S, Alewood PF, Birch CJ, Martin JL, Fairlie DP (2000) Synthesis, stability, antiviral activity, and protease-bound structures of substrate-mimicking constrained macrocyclic inhibitors of HIV-1 protease. J Med Chem 43:3495–3504CrossRefGoogle Scholar
  44. 44.
    Kervinen J, Lubkowski J, Zdanov A, Bhatt D, Dunn BM, Hui KY, Powell DJ, Kay J, Wlodawer A, Gustchina A (1998) Toward a universal inhibitor of retroviral proteases: comparative analysis of the interactions of LP-130 complexed with proteases from HIV-1, FIV, and EIAV. Protein Sci 7:2314–2323CrossRefGoogle Scholar
  45. 45.
    Dreyer GB, Lambert DM, Meek TD, Carr TJ, Tomaszek JTA, Fernandez AV, Bartus H, Cacciavillani E, Hassell AM, Minnich M, Petteway JSR, Metcalf BW (1992) Hydroxyethylene isostere inhibitors of human immunodeficiency virus-1 protease: structure-activity analysis using enzyme kinetics, X-ray crystallography, and infected T-cell assays. Biochemistry 31:6646–6659CrossRefGoogle Scholar
  46. 46.
    Lindberg J, Pyring D, Lowgren S, Rosenquist A, Zuccarello G, Kvarnstrom I, Zhang H, Vrang L, Classon B, Hallberg A, Samuelsson B, Unge T (2004) Symmetric fluoro-substituted diol-based HIV protease inhibitors: ortho-fluorinated and meta-fluorinated P1/P1′-benzyloxy side groups significantly improve the antiviral activity and preserve binding efficacy. Eur J Biochem 271:4594–4602CrossRefGoogle Scholar
  47. 47.
    Chellappan S, Kiran Kumar Reddy GS, Ali A, Nalam MN, Anjum SG, Cao H, Kairys V, Fernandes MX, Altman MD, Tidor B, Rana TM, Schiffer CA, Gilson MK (2007) Design of mutation-resistant HIV protease inhibitors with the substrate envelope hypothesis. Chem Biol Drug Des 69:298–313CrossRefGoogle Scholar
  48. 48.
    Jia Z, Ye Q, Dinaut AN, Wang Q, Waddleton D, Payette P, Ramachandran C, Kennedy B, Hum G, Taylor SD (2001) Structure of protein tyrosine phosphatase 1B in complex with inhibitors bearing two phosphotyrosine mimetics. J Med Chem 44:4584–4594CrossRefGoogle Scholar
  49. 49.
    Liu G, Xin Z, Liang H, Abad-Zapatero C, Hajduk PJ, Janowick DA, Szczepankiewicz BG, Pei Z, Hutchins CW, Ballaron SJ, Stashko MA, Lubben TH, Berg CE, Rondinone CM, Trevillyan JM, Jirousek MR (2003) Selective protein tyrosine phosphatase 1B inhibitors: Targeting the second phosphotyrosine binding site with non-carboxylic acid-containing ligand. J Med Chem 46:3437–3440CrossRefGoogle Scholar
  50. 50.
    Prabu-Jeyabalan M, Nalivaika EA, King NM, Schiffer CA (2003) Viability of a drug-resistant human immunodeficiency virus type 1 protease variant: Structural insights for better antiviral therapy. J Virol 77:1306–1315CrossRefGoogle Scholar
  51. 51.
    Pei Z, Li X, Liu G, Abad-Zapatero C, Lubben T, Zhang T, Ballaron SJ, Hutchins CW, Trevillyan JM, Jirousek M (2003) Discovery and SAR of novel, potent and selective protein tyrosine phosphatase 1B inhibitors. Bioorg Med Chem Lett 13:3129–3132CrossRefGoogle Scholar
  52. 52.
    Thanki N, Rao JK, Foundling SI, Howe WJ, Moon JB, Hui JO, Tomasselli AG, Heinrikson RL, Thaisrivongs S, Wlodawer A (1992) Crystal structure of a complex of HIV-1 protease with a dihydroxyethylene-containing inhibitor: Comparisons with molecular modeling. Protein Sci 1:1061–1072CrossRefGoogle Scholar
  53. 53.
    Scapin G, Patel SB, Becker JW, Wang Q, Desponts C, Waddleton D, Skorey K, Cromlish W, Bayly C, Therien M, Gauthier JY, Li CS, Lau CK, Ramachandran C, Kennedy BP, Asante-Appiah E (2003) The structural basis for the selectivity of benzotriazole inhibitors of PTP1B. Biochemistry 42:11451–11459CrossRefGoogle Scholar
  54. 54.
    Moretto AF, Kirincich SJ, Xu WX, Smith MJ, Wan ZK, Wilson DP, Follows BC, Binnun E, Joseph-McCarthy D, Foreman K, Erbe DV, Zhang YL, Tam SK, Tam SY, Lee J (2006) Bicyclic and tricyclic thiophenes as protein tyrosine phosphatase 1B inhibitors. Bioorg Med Chem 14:2162–2177CrossRefGoogle Scholar
  55. 55.
    Wan ZK, Lee J, Xu W, Erbe DV, Joseph-McCarthy D, Follows BC, Zhang YL (2006) Monocyclic thiophenes as protein tyrosine phosphatase 1B inhibitors: capturing interactions with Asp48. Bioorg Med Chem Lett 16:4941–4945CrossRefGoogle Scholar
  56. 56.
    Krohn A, Redshaw S, Ritchie JC, Graves BJ, Hatada MH (1991) Novel binding mode of highly potent HIV-proteinase inhibitors incorporating the (R)-hydroxyethylamine isostere. J Med Chem 34:3340–3342CrossRefGoogle Scholar
  57. 57.
    Smith AB III, Cantin LD, Pasternak A, Guise-Zawacki L, Yao W, Charnley AK, Barbosa J, Sprengeler PA, Hirschmann R, Munshi S, Olsen DB, Schleif WA, Kuo LC (2003) Design, synthesis, and biological evaluation of monopyrrolinone-based HIV-1 protease inhibitors. J Med Chem 46:1831–1844CrossRefGoogle Scholar
  58. 58.
    Wan ZK, Follows B, Kirincich S, Wilson D, Binnun E, Xu W, Joseph-McCarthy D, Wu J, Smith M, Zhang YL, Tam M, Erbe D, Tam S, Saiah E, Lee J (2007) Probing acid replacements of thiophene PTP1B inhibitors. Bioorg Med Chem Lett 17:2913–2920CrossRefGoogle Scholar

Copyright information

© Springer-Verlag 2010

Authors and Affiliations

  • Joshy P. Yesudas
    • 1
  • Fareed Bhasha Sayyed
    • 1
  • Cherumuttathu H. Suresh
    • 1
  1. 1.Computational Modeling and Simulation SectionNational Institute for Interdisciplinary Science and Technology (CSIR)TrivandrumIndia

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