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. 2001 Jan;80(1):121–129. doi: 10.1016/S0006-3495(01)75999-1

Molecular dynamics simulations of human rhinovirus and an antiviral compound.

B Speelman 1, B R Brooks 1, C B Post 1
PMCID: PMC1301218  PMID: 11159387

Abstract

The human rhinovirus 14 (HRV14) protomer, with or without the antiviral compound WIN 52084s, was simulated using molecular dynamics and rotational symmetry boundary conditions to model the effect of the entire icosahedral capsid. The protein asymmetrical unit, comprising four capsid proteins (VP1, VP2, VP3, and VP4) and two calcium ions, was solvated both on the exterior and the interior to fill the inside of the capsid. The stability of the simulations of this large system (~800 residues and 6,650 water molecules) is comparable to more conventional globular protein simulations. The influence of the antiviral compound on compressibility and positional fluctuations is reported. The compressibility, estimated from the density fluctuations in the region of the binding pocket, was found to be greater with WIN 52084s bound than without the drug, substantiating previous computations on reduced viral systems. An increase in compressibility correlates with an entropically more favorable system. In contrast to the increase in density fluctuations and compressibility, the positional fluctuations decreased dramatically for the external loops of VP1 and the N-terminus of VP3 when WIN 52084s is bound. Most of these VP1 and VP3 loops are found near the fivefold axis, a region whose mobility was not considered in reduced systems, but can be observed with this simulation of the full viral protomer. Altered loop flexibility is consistent with changes in proteolytic sensitivity observed experimentally. Moreover, decreased flexibility in these intraprotomeric loops is noteworthy since the externalization of VP4, part of VP1, and RNA during the uncoating process is thought to involve areas near the fivefold axis. Both the decrease in positional fluctuations at the fivefold axis and the increase in compressibility near the WIN pocket are discussed in relationship to the antiviral activity of stabilizing the virus against uncoating.

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Selected References

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  1. Badger J., Minor I., Kremer M. J., Oliveira M. A., Smith T. J., Griffith J. P., Guerin D. M., Krishnaswamy S., Luo M., Rossmann M. G. Structural analysis of a series of antiviral agents complexed with human rhinovirus 14. Proc Natl Acad Sci U S A. 1988 May;85(10):3304–3308. doi: 10.1073/pnas.85.10.3304. [DOI] [PMC free article] [PubMed] [Google Scholar]
  2. Belnap D. M., Filman D. J., Trus B. L., Cheng N., Booy F. P., Conway J. F., Curry S., Hiremath C. N., Tsang S. K., Steven A. C. Molecular tectonic model of virus structural transitions: the putative cell entry states of poliovirus. J Virol. 2000 Feb;74(3):1342–1354. doi: 10.1128/jvi.74.3.1342-1354.2000. [DOI] [PMC free article] [PubMed] [Google Scholar]
  3. Bibler-Muckelbauer J. K., Kremer M. J., Rossmann M. G., Diana G. D., Dutko F. J., Pevear D. C., McKinlay M. A. Human rhinovirus 14 complexed with fragments of active antiviral compounds. Virology. 1994 Jul;202(1):360–369. doi: 10.1006/viro.1994.1352. [DOI] [PubMed] [Google Scholar]
  4. Eads J., Sacchettini J. C., Kromminga A., Gordon J. I. Escherichia coli-derived rat intestinal fatty acid binding protein with bound myristate at 1.5 A resolution and I-FABPArg106-->Gln with bound oleate at 1.74 A resolution. J Biol Chem. 1993 Dec 15;268(35):26375–26385. [PubMed] [Google Scholar]
  5. Fox M. P., Otto M. J., McKinlay M. A. Prevention of rhinovirus and poliovirus uncoating by WIN 51711, a new antiviral drug. Antimicrob Agents Chemother. 1986 Jul;30(1):110–116. doi: 10.1128/aac.30.1.110. [DOI] [PMC free article] [PubMed] [Google Scholar]
  6. Fricks C. E., Hogle J. M. Cell-induced conformational change in poliovirus: externalization of the amino terminus of VP1 is responsible for liposome binding. J Virol. 1990 May;64(5):1934–1945. doi: 10.1128/jvi.64.5.1934-1945.1990. [DOI] [PMC free article] [PubMed] [Google Scholar]
  7. Grant R. A., Hiremath C. N., Filman D. J., Syed R., Andries K., Hogle J. M. Structures of poliovirus complexes with anti-viral drugs: implications for viral stability and drug design. Curr Biol. 1994 Sep 1;4(9):784–797. doi: 10.1016/s0960-9822(00)00176-7. [DOI] [PubMed] [Google Scholar]
  8. Hadfield A. T., Oliveira M. A., Kim K. H., Minor I., Kremer M. J., Heinz B. A., Shepard D., Pevear D. C., Rueckert R. R., Rossmann M. G. Structural studies on human rhinovirus 14 drug-resistant compensation mutants. J Mol Biol. 1995 Oct 13;253(1):61–73. doi: 10.1006/jmbi.1995.0536. [DOI] [PubMed] [Google Scholar]
  9. Harte W. E., Jr, Swaminathan S., Beveridge D. L. Molecular dynamics of HIV-1 protease. Proteins. 1992 Jul;13(3):175–194. doi: 10.1002/prot.340130302. [DOI] [PubMed] [Google Scholar]
  10. Hendry E., Hatanaka H., Fry E., Smyth M., Tate J., Stanway G., Santti J., Maaronen M., Hyypiä T., Stuart D. The crystal structure of coxsackievirus A9: new insights into the uncoating mechanisms of enteroviruses. Structure. 1999 Dec 15;7(12):1527–1538. doi: 10.1016/s0969-2126(00)88343-4. [DOI] [PubMed] [Google Scholar]
  11. Hogle J. M., Chow M., Filman D. J. Three-dimensional structure of poliovirus at 2.9 A resolution. Science. 1985 Sep 27;229(4720):1358–1365. doi: 10.1126/science.2994218. [DOI] [PubMed] [Google Scholar]
  12. Humphrey W., Dalke A., Schulten K. VMD: visual molecular dynamics. J Mol Graph. 1996 Feb;14(1):33-8, 27-8. doi: 10.1016/0263-7855(96)00018-5. [DOI] [PubMed] [Google Scholar]
  13. Kalko S. G., Cachau R. E., Silva A. M. Ion channels in icosahedral virus: a comparative analysis of the structures and binding sites at their fivefold axes. Biophys J. 1992 Oct;63(4):1133–1145. doi: 10.1016/S0006-3495(92)81693-4. [DOI] [PMC free article] [PubMed] [Google Scholar]
  14. Lewis J. K., Bothner B., Smith T. J., Siuzdak G. Antiviral agent blocks breathing of the common cold virus. Proc Natl Acad Sci U S A. 1998 Jun 9;95(12):6774–6778. doi: 10.1073/pnas.95.12.6774. [DOI] [PMC free article] [PubMed] [Google Scholar]
  15. Li Q., Yafal A. G., Lee Y. M., Hogle J., Chow M. Poliovirus neutralization by antibodies to internal epitopes of VP4 and VP1 results from reversible exposure of these sequences at physiological temperature. J Virol. 1994 Jun;68(6):3965–3970. doi: 10.1128/jvi.68.6.3965-3970.1994. [DOI] [PMC free article] [PubMed] [Google Scholar]
  16. Lybrand T. P., McCammon J. A. Computer simulation study of the binding of an antiviral agent to a sensitive and a resistant human rhinovirus. J Comput Aided Mol Des. 1989 Jan;2(4):259–266. doi: 10.1007/BF01532989. [DOI] [PubMed] [Google Scholar]
  17. Mosser A. G., Rueckert R. R. WIN 51711-dependent mutants of poliovirus type 3: evidence that virions decay after release from cells unless drug is present. J Virol. 1993 Mar;67(3):1246–1254. doi: 10.1128/jvi.67.3.1246-1254.1993. [DOI] [PMC free article] [PubMed] [Google Scholar]
  18. Muckelbauer J. K., Kremer M., Minor I., Diana G., Dutko F. J., Groarke J., Pevear D. C., Rossmann M. G. The structure of coxsackievirus B3 at 3.5 A resolution. Structure. 1995 Jul 15;3(7):653–667. doi: 10.1016/s0969-2126(01)00201-5. [DOI] [PubMed] [Google Scholar]
  19. Müller C. W., Schlauderer G. J., Reinstein J., Schulz G. E. Adenylate kinase motions during catalysis: an energetic counterweight balancing substrate binding. Structure. 1996 Feb 15;4(2):147–156. doi: 10.1016/s0969-2126(96)00018-4. [DOI] [PubMed] [Google Scholar]
  20. Olson N. H., Kolatkar P. R., Oliveira M. A., Cheng R. H., Greve J. M., McClelland A., Baker T. S., Rossmann M. G. Structure of a human rhinovirus complexed with its receptor molecule. Proc Natl Acad Sci U S A. 1993 Jan 15;90(2):507–511. doi: 10.1073/pnas.90.2.507. [DOI] [PMC free article] [PubMed] [Google Scholar]
  21. Pevear D. C., Fancher M. J., Felock P. J., Rossmann M. G., Miller M. S., Diana G., Treasurywala A. M., McKinlay M. A., Dutko F. J. Conformational change in the floor of the human rhinovirus canyon blocks adsorption to HeLa cell receptors. J Virol. 1989 May;63(5):2002–2007. doi: 10.1128/jvi.63.5.2002-2007.1989. [DOI] [PMC free article] [PubMed] [Google Scholar]
  22. Pevear D. C., Tull T. M., Seipel M. E., Groarke J. M. Activity of pleconaril against enteroviruses. Antimicrob Agents Chemother. 1999 Sep;43(9):2109–2115. doi: 10.1128/aac.43.9.2109. [DOI] [PMC free article] [PubMed] [Google Scholar]
  23. Phelps D. K., Post C. B. A novel basis of capsid stabilization by antiviral compounds. J Mol Biol. 1995 Dec 8;254(4):544–551. doi: 10.1006/jmbi.1995.0637. [DOI] [PubMed] [Google Scholar]
  24. Phelps D. K., Post C. B. Molecular dynamics investigation of the effect of an antiviral compound on human rhinovirus. Protein Sci. 1999 Nov;8(11):2281–2289. doi: 10.1110/ps.8.11.2281. [DOI] [PMC free article] [PubMed] [Google Scholar]
  25. Phelps D. K., Rossky P. J., Post C. B. Influence of an antiviral compound on the temperature dependence of viral protein flexibility and packing: a molecular dynamics study. J Mol Biol. 1998 Feb 20;276(2):331–337. doi: 10.1006/jmbi.1997.1542. [DOI] [PubMed] [Google Scholar]
  26. Phelps D. K., Speelman B., Post C. B. Theoretical studies of viral capsid proteins. Curr Opin Struct Biol. 2000 Apr;10(2):170–173. doi: 10.1016/s0959-440x(00)00064-6. [DOI] [PubMed] [Google Scholar]
  27. Post C. B., Brooks B. R., Karplus M., Dobson C. M., Artymiuk P. J., Cheetham J. C., Phillips D. C. Molecular dynamics simulations of native and substrate-bound lysozyme. A study of the average structures and atomic fluctuations. J Mol Biol. 1986 Aug 5;190(3):455–479. doi: 10.1016/0022-2836(86)90015-x. [DOI] [PubMed] [Google Scholar]
  28. Rombaut B., Andries K., Boeyé A. A comparison of WIN 51711 and R 78206 as stabilizers of poliovirus virions and procapsids. J Gen Virol. 1991 Sep;72(Pt 9):2153–2157. doi: 10.1099/0022-1317-72-9-2153. [DOI] [PubMed] [Google Scholar]
  29. Rossmann M. G., Arnold E., Erickson J. W., Frankenberger E. A., Griffith J. P., Hecht H. J., Johnson J. E., Kamer G., Luo M., Mosser A. G. Structure of a human common cold virus and functional relationship to other picornaviruses. Nature. 1985 Sep 12;317(6033):145–153. doi: 10.1038/317145a0. [DOI] [PubMed] [Google Scholar]
  30. Smith T. J., Baker T. Picornaviruses: epitopes, canyons, and pockets. Adv Virus Res. 1999;52:1–23. doi: 10.1016/s0065-3527(08)60297-3. [DOI] [PubMed] [Google Scholar]
  31. Smith T. J., Kremer M. J., Luo M., Vriend G., Arnold E., Kamer G., Rossmann M. G., McKinlay M. A., Diana G. D., Otto M. J. The site of attachment in human rhinovirus 14 for antiviral agents that inhibit uncoating. Science. 1986 Sep 19;233(4770):1286–1293. doi: 10.1126/science.3018924. [DOI] [PubMed] [Google Scholar]
  32. Tsang S. K., Danthi P., Chow M., Hogle J. M. Stabilization of poliovirus by capsid-binding antiviral drugs is due to entropic effects. J Mol Biol. 2000 Feb 18;296(2):335–340. doi: 10.1006/jmbi.1999.3483. [DOI] [PubMed] [Google Scholar]
  33. Vaidehi N., Goddard W. A., 3rd The pentamer channel stiffening model for drug action on human rhinovirus HRV-1A. Proc Natl Acad Sci U S A. 1997 Mar 18;94(6):2466–2471. doi: 10.1073/pnas.94.6.2466. [DOI] [PMC free article] [PubMed] [Google Scholar]
  34. Young A. C., Scapin G., Kromminga A., Patel S. B., Veerkamp J. H., Sacchettini J. C. Structural studies on human muscle fatty acid binding protein at 1.4 A resolution: binding interactions with three C18 fatty acids. Structure. 1994 Jun 15;2(6):523–534. doi: 10.1016/s0969-2126(00)00052-6. [DOI] [PubMed] [Google Scholar]
  35. Zhao R., Hadfield A. T., Kremer M. J., Rossmann M. G. Cations in human rhinoviruses. Virology. 1997 Jan 6;227(1):13–23. doi: 10.1006/viro.1996.8301. [DOI] [PubMed] [Google Scholar]

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