Skip to main content
PMC home page
Wiley - PMC COVID-19 Collection logoLink to Wiley - PMC COVID-19 Collection
. 2013 Sep 25;51(5A):889–900. doi: 10.1002/jccs.200400134

Homology Models and Molecular Dynamics Simulations of Main Proteinase from Coronavirus Associated with Severe Acute Respiratory Syndrome (SARS)

Hsuan‐Liang Liu 1,✉, Jin‐Chung Lin 1, Yih Ho 2, Wei‐Chan Hsieh 1, Chin‐Wen Chen 1, Yuan‐Chen Su 1
PMCID: PMC7167048  PMID: 32336761

Abstract

In this study, two structural models (denoted as MproST and MproSH) of the main proteinase (Mpro) from the novel coronavirus associated with severe acute respiratory syndrome (SARS‐CoV) were constructed based on the crystallographic structures of Mpro from transmissible gastroenteritis coronavirus (TGEV) (MproT) and human coronavirus HcoV‐229E (MproH), respectively. Various 200 ps molecular dynamics simulations were subsequently performed to investigate the dynamics behaviors of several structural features. Both MproST and MproSH exhibit similar folds as their respective template proteins. These structural models reveal three distinct functional domains as well as an intervening loop connecting domains II and III as found in both template proteins. In addition, domain III of these structures exhibits the least secondary structural conservation. A catalytic cleft containing the substrate binding subsites S1 and the S2 between domains I and II are also observed in these structural models. Although these structures share many common features, the most significant difference occurs at the S2 subsite, where the amino acid residues lining up this subsite are least conserved. It may be a critical challenge for designing anti‐SARS drugs by simply screening the known database of proteinase inhibitors.

Keywords: Main proteinase, Coronavirus, Severe acute respiratory syndrome (SARS), Molecular dynamics simulations, Functional domain, Structural model, Inhibitor

References

  • 1. Drosten, C. ; Günther, S. ; Preiser, W. ; van der Werf, S. ; Brodt, H.‐R. ; Becker, S. ; Rabenau, H. ; Panning, M. ; Kolesnikova, L. ; Fouchier, R. A. M. ; Berger, A. ; Burguière, A.‐M. ; Cinatl, J. ; Eickmann, M. ; Escriou, N. ; Grywna, K. ; Kramme, S. ; Manuguerra, J.‐C. ; Müller, S. ; Rickerts, V. ; Stürmer, M. ; Vieth, S. ; Klenk, H.‐D. ; Osterhaus, A. D. M. E. ; Schmitz, H. M. D. ; Doer, H. W. N. Engl. J. Med. 2003, 348, 1967. [DOI] [PubMed] [Google Scholar]
  • 2. Ksiazek, T. G. ; Erdman, D. ; Goldsmith, C. S. ; Zaki, S. R. ; Peret, T. ; Emery, S. ; Tong, S. ; Urbani, C. ; Comer, J. A. ; Lim, W. ; Rollin, P. E. ; Dowell, S. F. ; Ling, A.‐E. ; Humphrey, C. D. ; Shieh, W.‐J. ; Guarner, J. ; Paddock, C. D. ; Rota, P. ; Fields, B. ; DeRisi, J. ; Yang, J.‐Y. ; Cox, N. ; Hughes, J. M. ; LeDuc, J. W. ; Bellini, W. J. ; Anderson, L. J. N. Engl. J. Med. 2003, 348, 1953. [DOI] [PubMed] [Google Scholar]
  • 3. Lee, N. ; Hui, D. ; Wu, A. ; Chan, P. ; Cameron, P. ; Joynt, G. M. ; Ahuja, A. ; Yung, M. Y. ; Leung, C. B. ; To, K. F. ; Lui, S. F. ; Szeto, C. C. ; Chung, S. ; Sung, J. J. Y. N. Engl. J. Med. 2003, 348, 1986. [DOI] [PubMed] [Google Scholar]
  • 4. Marra, M. A. ; Jones, S. J. M. ; Astell, C. R. ; Holt, R. A. ; Brooks‐Wilson, A. ; Butterfield, Y. S. N. ; Khattra, J. ; Asano, J. K. ; Barber, S. A. ; Chan, S. Y. ; Cloutier, A. ; Coughlin, S. M. ; Freeman, D. ; Girn, N. ; Griffith, O. L. ; Leach, S. R. ; Mayo, M. ; McDonald, H. ; Montgomery, S. B. ; Pandoh, P. K. ; Petrescu, A. S. ; Robertson, A. G. ; Schein, J. E. ; Siddiqui, A. ; Smailus, D. E. ; Stott, J. M. ; Yang, G. S. Science 2003, 300, 1399. [DOI] [PubMed] [Google Scholar]
  • 5. Rota, P. A. ; Oberste, M. S. ; Monroe, S. S. ; Nix, W. A. ; Compagnoli, R. ; Icenogle, J. P. ; Peñaranda, S. ; Bankamp, B. ; Maher, K. ; Chen, M.‐H. ; Tong, S. ; Tamin, A. ; Lowe, L. ; Frace, M. ; DeRisi, J. L. ; Chen, Q. ; Wang, D. ; Erdman, D. D. ; Peret, T. C. T. ; Burns, C. ; Ksiazek, T. G. ; Rollin, P. E. ; Sanchez, A. ; Liffick, S. ; Holloway, B. ; Limor, J. ; McCaustland, K. ; Olsen‐Rassmussen, M. ; Fouchier, R. ; Günther, S. ; Osterhaus, A. D. M. E. ; Drosten, C. ; Pallansch, M. P. ; Anderson, L. J. ; Bellini, W. J. Science 2003, 300, 1394. [DOI] [PubMed] [Google Scholar]
  • 6. Enjuanes, L. et al.; van Regenmortal, M. H. V. ; Fauqet, C. M. ; Bishop, D. H. L. ; Carstens, E. B. ; Rstes, M. K. ; Lemon, S. M. ; Mayo, M. A. ; McGeoch, D. J. ; Pringle, C. R. In Virus Taxonomy; Wickner R. B., Ed.; Academic Press: New York, 2000; pp 835–849. [Google Scholar]
  • 7. Holm, L. ; Sander, C. J. Mol. Biol. 1993, 233, 123. [DOI] [PubMed] [Google Scholar]
  • 8. Lai, M. M. C. ; Holmes, K. V. In Fields Virology; Knipe D. M.; Howley P. M., Ed.; Lippincott Williams and Wilkins: New York, 2001; Chapter 35. [Google Scholar]
  • 9. Myint, S. H. In The Coronavirdae; Siddell S. G., Ed.; Plenum Press: New York, 1995; p 389. [Google Scholar]
  • 10. Cavanagh, D. Arch. Virol. 1997, 142, 629. [PubMed] [Google Scholar]
  • 11. Den Boon, J. A. ; Snijder, E. J. ; Chirnside, E. D. ; de Vries, A. A. ; Horzinek, M. C. ; Spaan, W. J. J. Virol. 1991, 65, 2910. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 12. Herold, J. ; Raabe, T. ; Schelle‐Prinz, B. ; Siddell, S. G. Virology 1993, 195, 680. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 13. Thiel, V. ; Herold, J. ; Schelle, B. ; Siddell, S. G. J. Virol. 2001, 75, 6676. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 14. Ziebuhr, J. ; Herold, J. ; Siddell, S. G. J. Virol. 1995, 69, 4331. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 15. Gornalenya, A. E. ; Donchenko, A. P. ; Blinov, V. M. ; Koonin, E. V. FEBS Lett. 1989, 243, 103. [DOI] [PubMed] [Google Scholar]
  • 16. Gornalenya, A. E. ; Koonin, E. V. ; Donchenko, A. P. ; Blinov, V. M. Nucleic Acids Res. 1989, 17, 4847. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 17. Ziebuhr, J. ; Heusipp, G. ; Siddell, S. G. J. Virol. 1997, 71, 3992. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 18. Hegyi, A. ; Friebe, A. ; Gorbalenya, A. E. ; Ziebuhr, J. J. Gen. Virol. 2002, 83, 581. [DOI] [PubMed] [Google Scholar]
  • 19. Liu, D. X. ; Brown, T. D. Virology 1995, 209, 420. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 20. Lu, Y. ; Denison, M. R. Virology 1997, 230, 335. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 21. Ziebuhr, J. ; Snijder, E. J. ; Gorbalenya, A. E. J. Gen. Virol. 2000, 81, 853. [DOI] [PubMed] [Google Scholar]
  • 22. Hegyi, A. ; Ziebuhr, J. J. Gen. Virol. 2002, 83, 595. [DOI] [PubMed] [Google Scholar]
  • 23. Anand, K. ; Ziebuhr, J. ; Wadhwani, P. ; Mesters, J. R. ; Hilgenfeld, R. Science 2003, 300, 1763. [DOI] [PubMed] [Google Scholar]
  • 24. Ponder, J. W. ; Richards, F. M. J. Mol. Biol. 1987, 193, 775. [DOI] [PubMed] [Google Scholar]
  • 25. Xiong, B. ; Gui, C.‐S. ; Xu, X.‐Y. ; Luo, C. ; Chen, J. ; Luo, H.‐B. ; Chen, L.‐L. ; Li, G.‐W. ; Sun, T. ; Yu, C.‐Y. ; Yue, L.‐D. ; Duan, W.‐H. ; Shen, J.‐K. ; Qin, L. ; Shi, T.‐L. ; Li, Y.‐X. ; Chen, K.‐X. ; Luo, X.‐M. ; Shen, X. ; Shen, J.‐H. ; Jiang, H.‐L. Acta Pharmacol. Sin. 2003, 24, 497. [PubMed] [Google Scholar]
  • 26. Anand, K. ; Palm, G. J. ; Mesters, J. R. ; Siddell, S. G. ; Ziebuhr, J. ; Hilgenfeld, R. EMBO J. 2002, 21, 3213. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 27. Liu, H.‐L. ; Wang, W.‐C. Chem. Phys. Lett. 2002, 366, 284. [Google Scholar]
  • 28. Liu, H.‐L. ; Wang, W.‐C. Protein Eng. 2003, 16, 19. [DOI] [PubMed] [Google Scholar]
  • 29. Liu, H.‐L. ; Wang, W.‐C. J. Biomol. Struct. Dyn. 2003, 20, 615. [DOI] [PubMed] [Google Scholar]
  • 30. Liu, H.‐L. ; Lin, Y.‐M. J. Chin. Chem. Soc. 2003, 50, 799. [Google Scholar]
  • 31. Liu, H.‐L. ; Hsu, C.‐M. J. Chin. Chem. Soc. 2003, 50, 1235. [Google Scholar]
  • 32. Liu, H.‐L. ; Lin, J.‐C. Chem. Phys. Lett. 2003, 381, 592. [Google Scholar]
  • 33. Liu, H.‐L. ; Lin, J.‐C. J. Biomol. Struct. Dyn. 2004, 21, 639. [DOI] [PubMed] [Google Scholar]
  • 34. Hwang, M.‐J. ; Ni, X. ; Waldman, M. ; Ewig, C. S. ; Hagler, A. T. Biopolymers 1998, 45, 435. [DOI] [PubMed] [Google Scholar]
  • 35. Maple, J. R. ; Hwang, M.‐J. ; Jalkanen, K. J. ; Stockfisch, T. P. ; Hagler, A. T. J. Comp. Chem. 1998, 19, 430. [Google Scholar]
  • 36. Peng, Z. ; Ewig, C. S. ; Hwang, M.‐J. ; Waldman, M. ; Hagler, A. T. J. Phys. Chem. A 1997, 101, 7243. [Google Scholar]
  • 37. Greer, J. Proteins 1990, 7, 317. [DOI] [PubMed] [Google Scholar]
  • 38. Schuler, G. D. ; Altschul, S. F. ; Lipman, D. J. Proteins: Struct. Funct. Genet. 1991, 9, 180. [DOI] [PubMed] [Google Scholar]
  • 39. Shenkin, P. S. ; Yarmush, D. L. ; Fine, R. M. ; Wang, H. ; Levinthal, C. Biopolymers 1987, 26, 2053. [DOI] [PubMed] [Google Scholar]
  • 40. Kabsch, W. ; Sander, C. Biopolymers 1983, 22, 2577. [DOI] [PubMed] [Google Scholar]
  • 41. Berendsen, H. J. C. ; Postma, J. P. M. ; van Gunsteren, W. F. ; DiNola, A. ; Haak, J. R. J. Comp. Phys. 1984, 81, 3684. [Google Scholar]
  • 42. Lesk, A. M. Proteins 1998, 33, 320. [PubMed] [Google Scholar]
  • 43. Levitt, M. ; Gerstein, M. Proc. Natl. Acad. Sci. USA 1998, 95, 5913. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 44. Mizuguchi, K. ; Go, N. Curr. Opin. Struct. Biol. 1995, 5, 377. [DOI] [PubMed] [Google Scholar]
  • 45. Koehi, P. Curr. Opin. Struct. Biol. 2001, 11, 348. [DOI] [PubMed] [Google Scholar]
  • 46. Kabsch, W. Acta Cryst. A 1976, 32, 922. [Google Scholar]
  • 47. Siddell, S. G. In The Coronavirdae; Siddell S. G., Ed.; Plenum Press: New York, 1995; p 1. [Google Scholar]
  • 48. Allaire, M. ; Chernaia, M. M. ; Malcolm, B. A. ; James, M. N. Nature 1994, 369, 72. [DOI] [PubMed] [Google Scholar]
  • 49. Bergmann, E. M. ; Mosimann, S. C. ; Chernaia, M. M. ; Malcolm, B. A. ; James, M. N. J. Virol. 1997, 72, 2436. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 50. Tsukada, H. ; Blow, D. M. J. Mol. Biol. 1985, 184, 703. [DOI] [PubMed] [Google Scholar]
  • 51. Gilbert, D. ; Westhead, D. ; Nagano, N. ; Thornton, J. Bioinformatics 1999, 15, 317. [DOI] [PubMed] [Google Scholar]
  • 52. Mosimann, S. C. ; Cherney, M. M. ; Sia, S. ; Plotch, S. ; James, M. N. J. Mol. Biol. 1997, 273, 1032. [DOI] [PubMed] [Google Scholar]
  • 53. Kamphuis, I. G. ; Kalk, K. H. ; Swarte, M. B. ; Drenth, J. J. Mol. Biol. 1984, 179, 233. [DOI] [PubMed] [Google Scholar]
  • 54. Polgár, L. FEBS Lett. 1974, 47, 15. [DOI] [PubMed] [Google Scholar]
  • 55. Malcolm, B. A. Protein Sci. 1995, 4, 1439. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 56. Matthews, D. A. et al., Cell 1994, 77, 761. [DOI] [PubMed] [Google Scholar]
  • 57. Petersen, J. F. ; Cherney, M. M. ; Liebig, H. D. ; Skern, T. ; Kuechler, E. ; James, M. N. EMBO J. 1999, 18, 5463. [DOI] [PMC free article] [PubMed] [Google Scholar]

Articles from Journal of the Chinese Chemical Society. Zhongguo Hua Xue Hui (Taipei, Taiwan) are provided here courtesy of Wiley

RESOURCES