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. 1999 Nov;8(11):2281–2289. doi: 10.1110/ps.8.11.2281

Molecular dynamics investigation of the effect of an antiviral compound on human rhinovirus.

D K Phelps 1, C B Post 1
PMCID: PMC2144186  PMID: 10595531

Abstract

The factors that influence the enhanced stability observed experimentally of human rhinovirus 14 (HRV14) upon binding a hydrophobic antiviral drug have been investigated by molecular dynamics. Simulations centered about the HRV14 drug-binding pocket allow the reliable assessment of differences in capsid protein motions of HRV14 and drug-bound HRV14. We propose that the experimentally observed stabilization of the ligated virus arises from higher entropy, rather than enthalpy. Time-averaged interaction energies between the viral protein and molecules occupying the pocket are less favorable in the presence of the drug, consistent with the proposal that the observed stability arises from entropic effects. Interaction energies characterizing subunit-subunit contacts within one viral protomer are found to be substantially stronger than those between two protomers. Such distinction in subunit interaction would have clear implications on assembly and disassembly. Drug binding is found to affect large-scale, collective properties, while leaving local atomic properties unperturbed. Specifically, the simulations reveal a weakening of long-range correlations in atomic motions upon drug binding. On the other hand, neither the fast time scale RMS fluctuations of individual atomic positions nor the fluctuation build-up curves from the capsid beta-sandwich forming the drug-binding pocket show a consistent distinction between the drug-bound and drug-free viral simulations. Collectively, the detailed description available from the simulations provides an understanding of the experimental observations on the drug-induced changes in thermal stability and protease sensitivity reported for picornaviruses. The predicted significance of binding entropy can be explored experimentally and should be considered in the design of new antiviral compounds.

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Selected References

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  1. 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]
  2. Brooks C. L., 3rd, Karplus M. Solvent effects on protein motion and protein effects on solvent motion. Dynamics of the active site region of lysozyme. J Mol Biol. 1989 Jul 5;208(1):159–181. doi: 10.1016/0022-2836(89)90093-4. [DOI] [PubMed] [Google Scholar]
  3. Daggett V., Levitt M. Realistic simulations of native-protein dynamics in solution and beyond. Annu Rev Biophys Biomol Struct. 1993;22:353–380. doi: 10.1146/annurev.bb.22.060193.002033. [DOI] [PubMed] [Google Scholar]
  4. Filman D. J., Syed R., Chow M., Macadam A. J., Minor P. D., Hogle J. M. Structural factors that control conformational transitions and serotype specificity in type 3 poliovirus. EMBO J. 1989 May;8(5):1567–1579. doi: 10.1002/j.1460-2075.1989.tb03541.x. [DOI] [PMC free article] [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. 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]
  7. Ichiye T., Karplus M. Collective motions in proteins: a covariance analysis of atomic fluctuations in molecular dynamics and normal mode simulations. Proteins. 1991;11(3):205–217. doi: 10.1002/prot.340110305. [DOI] [PubMed] [Google Scholar]
  8. Kim K. H., Willingmann P., Gong Z. X., Kremer M. J., Chapman M. S., Minor I., Oliveira M. A., Rossmann M. G., Andries K., Diana G. D. A comparison of the anti-rhinoviral drug binding pocket in HRV14 and HRV1A. J Mol Biol. 1993 Mar 5;230(1):206–227. doi: 10.1006/jmbi.1993.1137. [DOI] [PubMed] [Google Scholar]
  9. 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]
  10. 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]
  11. 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]
  12. 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]
  13. Post C. B., Dobson C. M., Karplus M. A molecular dynamics analysis of protein structural elements. Proteins. 1989;5(4):337–354. doi: 10.1002/prot.340050409. [DOI] [PubMed] [Google Scholar]
  14. Reddy V. S., Giesing H. A., Morton R. T., Kumar A., Post C. B., Brooks C. L., 3rd, Johnson J. E. Energetics of quasiequivalence: computational analysis of protein-protein interactions in icosahedral viruses. Biophys J. 1998 Jan;74(1):546–558. doi: 10.1016/S0006-3495(98)77813-0. [DOI] [PMC free article] [PubMed] [Google Scholar]
  15. 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]
  16. 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]
  17. Rossmann M. G. Viral cell recognition and entry. Protein Sci. 1994 Oct;3(10):1712–1725. doi: 10.1002/pro.5560031010. [DOI] [PMC free article] [PubMed] [Google Scholar]
  18. 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]

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