Skip to main content
SpringerLink
Log in

Theoretical insight into sulfur–aromatic interactions with extension to D2 receptor activation mechanism

  • Original Research
  • Published:
Structural Chemistry Aims and scope Submit manuscript

Abstract

Contacts between aromatic rings and sulfur-containing amino acids are frequent in proteins. However, little is known about the nature of their interactions particularly if substituents are present on aromatic ring. In this paper, DFT quantum chemical calculations were used to study substituted benzenes in complex with hydrogen sulfide (H2S), methanethiol (CH3SH), and (Methylsulfanyl)methane (CH3SCH3). It was found that SH···π interaction is more stabilizing than the S···π interaction in the case of benzene, but this is changed with increasing electronegativity of the substituent on benzene ring. Although the change of energy of SH···π and S···π interaction follows the conventional model of substituent effect, where S···π interactions are maximized and SH···π interactions are diminished with electron-withdrawing substituent on benzene as a result of changes in the aryl π-system, it was found that it is mainly a consequence of direct electrostatic interaction between substituent and the sulfur-containing molecule. We also investigated the model system of Cys···Trp interaction, adjacent to a cluster of aromatic amino acids, in proteins, using explicit membrane molecular dynamics simulations results of D3 dopamine receptor crystal structure as starting point. It was found that fluorination in aromatic cluster enhances the Cys···Trp interaction. The effect is maximized when transferred through the rest of aromatic system suggesting possible explanation for frequent contacts between sulfur-containing and aromatic amino acids in proteins and their effects on protein folding and stabilization.

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

Access this article

Log in via an institution

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
Fig. 7
Fig. 8
Fig. 9
Fig. 10
Fig. 11
Fig. 12
Fig. 13
Fig. 14
Fig. 15
Fig. 16

Similar content being viewed by others

References

  1. Morgan RS, Tatsch CE, Gushard RH, McAdon J, Warme PK (1978) Int J Pept Prot Res 11:209–217

    Article  CAS  Google Scholar 

  2. Bodner BL, Jackman LM, Morgan RS (1980) Biochem Biophys Res Commun 94:807–813

    Article  CAS  Google Scholar 

  3. Pal D, Chakrabarti P (2001) J Biomol Struct Dyn 19:115–128

    Article  CAS  Google Scholar 

  4. Cordomi A, Gomez-Tamayo JC, Gigoux V, Fourmy D (2013) Trends Pharmacol Sci 34(6):320–331

    Article  CAS  Google Scholar 

  5. Duan G, Smith VH Jr, Weaver DF (2001) Mol Phys 19:1689–1699

    Article  Google Scholar 

  6. Meyer EA, Castellano RK, Diederich F (2003) Angew Chem Int Ed 42(11):1210–1250

    Article  CAS  Google Scholar 

  7. Tatko CD, Waters ML (2004) Protein Sci 13(9):2515–2522

    Article  CAS  Google Scholar 

  8. Tauer TP, Derrick ME, Sherrill CD (2005) J Phys Chem A 109:191–196

    Article  CAS  Google Scholar 

  9. Yan S, Lee SJ, Kang S, Choi KH, Rhee SK, Lee JY (2007) Bull Korean Chem Soc 28(6):959–964

    Article  CAS  Google Scholar 

  10. Ringer AL, Senenko A, Sherrill CD (2007) Protein Sci 16:2216–2223

    Article  CAS  Google Scholar 

  11. Wheeler SE (2013) Acc Chem Res 46:1029–1038

    Article  CAS  Google Scholar 

  12. Wheeler SE, Houk KN (2008) J Am Chem Soc 130:10854–10855

    Article  CAS  Google Scholar 

  13. Valley CC, Cembran A, Perlmutter JD, Lewis AK, Labello NP, Gao J, Sachs JN (2012) J Biol Chem 287(42):34979–34991

    Article  CAS  Google Scholar 

  14. Daeffler KNM, Laster HA, Dougherty DA (2012) J Am Chem Soc 134:14890–14896

    Article  CAS  Google Scholar 

  15. Grimme S (2006) J Comput Chem 27:1787–1799

    Article  CAS  Google Scholar 

  16. Schaefer A, Horn H, Ahlrichs R (1992) J Chem Phys 97:2571–2577

    Article  CAS  Google Scholar 

  17. Schaefer A, Huber C, Ahlrichs R (1994) J Chem Phys 100:5829–5835

    Article  CAS  Google Scholar 

  18. Frisch MJ, Trucks GW, Schlegel HB, Scuseria GE, Robb MA, Cheeseman JR, Scalmani G, Barone V, Mennucci B, Petersson GA, Nakatsuji H, Caricato M, Li X, Hratchian HP, Izmaylov AF, Bloino J, Zheng G, Sonnenberg JL, Hada M, Ehara M, Toyota K, Fukuda R, Hasegawa J, Ishida M, Nakajima T, Honda Y, Kitao O, Nakai H, Vreven T, Montgomery JA Jr, Peralta JE, Ogliaro F, Bearpark M, Heyd JJ, Brothers E, Kudin KN, Staroverov VN, Kobayashi R, Normand J, Raghavachari K, Rendell A, Burant JC, Iyengar SS, Tomasi J, Cossi M, Rega N, Millam JM, Klene M, Knox JE, Cross JB, Bakken V, Adamo C, Jaramillo J, Gomperts R, Stratmann RE, Yazyev O, Austin AJ, Cammi R, Pomelli C, Ochterski JW, Martin RL, Morokuma K, Zakrzewski VG, Voth GA, Salvador P, Dannenberg JJ, Dapprich S, Daniels AD, Farkas Ö, Foresman JB, Ortiz JV, Cioslowski J, Fox DJ (2009) Gaussian 09, Revision A.02. Gaussian Inc, Wallingford CT

    Google Scholar 

  19. Phillips JC, Braun R, Wang W, Gumbart J, Tajkhorshid E, Villa E, Chipot C, Skeel RD, Kale L, Schulten K (2005) J Comput Chem 26:1781–1802

    Article  CAS  Google Scholar 

  20. Chien EYT, Liu W, Zhao Q, Katritch V, Won Han G, Hanson MA, Shi L, Newman AH, Javitch JA, Cherezov V, Stevens RC (2010) Structure of the human dopamine D3 receptor in complex with a D2/D3 selective antagonist. Science 330(6007):1091–1095

    Article  CAS  Google Scholar 

  21. Humphrey W, Dalke A, Schulten K (1996) J. Mol Graph 14:33–38

    Article  CAS  Google Scholar 

  22. MacKerell AD Jr, Feig M, Brooks CL (2004) J Comput Chem 25:1400–1415

    Article  CAS  Google Scholar 

  23. MacKerell AD Jr, Bashford D, Bellott M, Dunbrack RL Jr, Evanseck JD, Field MJ, Fischer S, Gao J, Guo H, Ha S, Joseph- McCarthy D, Kuchnir L, Kuczera K, Lau FTK, Mattos C, Michnick S, Ngo T, Nguyen DT, Prodhom B, Reiher WE III, Roux B, Schlenkrich M, Smith JC, Stote R, Straub J, Wiorkiewicz-Kuczera J, Watanabe M, Yin D, Karplus M (1998) All-atom empirical potential for molecular modeling and dynamics studies of proteins. J Phys Chem B. 102:3586–3616

    Article  CAS  Google Scholar 

  24. Feller SE, Gawrisch G, MacKerell AD Jr (2002) J Am Chem Soc 124:318–326

    Article  CAS  Google Scholar 

  25. Feller S, MacKerell AD Jr (2000) J Phys Chem B 104:7510–7515

    Article  CAS  Google Scholar 

  26. PARADOX cluster at the Scientific Computing Laboratory of the Institute of Physics Belgrade, supported in part by the Serbian Ministry of Education and Science under project No. ON171017, and by the European Commission under FP7 projects HP-SEE, PRACE-1IP, PRACE-2IP, EGI-InSPIRE

  27. Origin (OriginLab, Northampton, MA). http://www.originlab.com/index.aspx?go=Company&pid=1130

  28. Accelrys Software Inc. (2007) Discovery Studio Viewer, Release 3.5. Accelrys Software Inc., San Diego. http://accelrys.com/products/discovery-studio/

  29. Persistence of Vision Pty. Ltd. (2004) Persistence of Vision Raytracer (Version 3.6) [Computer software]. http://www.povray.org/documentation/view/3.6.0/203/. Accesed 2 Dec 2014

  30. Adobe Photoshop 7 (2002) Adobe Systems Inc. http://www.adobe.com/products/photoshopfamily.html. Accesed 2 Dec 2014

  31. Dennington Roy, Keith Todd, Millam John (2009) GaussView, version 5. Semichem Inc., Shawnee Mission, KS

    Google Scholar 

  32. Hansch C, Leo A (1979) Substituent constants for correlation analysis in chemistry and biology. Wiley-Interscience, New York

    Google Scholar 

Download references

Acknowledgments

This work was supported by the Ministry of Education and Science of the Republic of Serbia (Grant No. OI172032).

Author information

Authors and Affiliations

  1. ICTM, Center of Chemistry, University of Belgrade, Studentski trg 12-16, P.O. Box 51, 11158, Belgrade, Serbia

    Ljiljana Došen-Mićović, Vladimir Šukalović & Sladjana Kostić-Rajačić

  2. Innovation Center of the Faculty of Chemistry, University of Belgrade, Studentski trg 12-16, P.O. Box 51, 11158, Belgrade, Serbia

    Milan Senćanski

Authors
  1. Milan Senćanski
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Ljiljana Došen-Mićović
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Vladimir Šukalović
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Sladjana Kostić-Rajačić
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Milan Senćanski.

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Senćanski, M., Došen-Mićović, L., Šukalović, V. et al. Theoretical insight into sulfur–aromatic interactions with extension to D2 receptor activation mechanism. Struct Chem 26, 1139–1149 (2015). https://doi.org/10.1007/s11224-015-0574-z

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s11224-015-0574-z

Keywords

Search

Navigation