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The European Physical Journal Special Topics

, Volume 225, Issue 8–9, pp 1757–1774 | Cite as

Breaking a virus: Identifying molecular level failure modes of a viral capsid by multiscale modeling

  • V. Krishnamani
  • C. Globisch
  • C. Peter
  • M. DesernoEmail author
Regular Article Specific Models to Tackle Fundamental Questions
Part of the following topical collections:
  1. Modern Simulation Approaches in Soft Matter Science: From Fundamental Understanding to Industrial Applications

Abstract

We use coarse-grained (CG) simulations to study the deformation of empty Cowpea Chlorotic Mottle Virus (CCMV) capsids under uniaxial compression, from the initial elastic response up to capsid breakage. Our CG model is based on the MARTINI force field and has been amended by a stabilizing elastic network, acting only within individual proteins, that was tuned to capture the fluctuation spectrum of capsid protein dimers, obtained from all atom simulations. We have previously shown that this model predicts force-compression curves that match AFM indentation experiments on empty CCMV capsids. Here we investigate details of the actual breaking events when the CCMV capsid finally fails. We present a symmetry classification of all relevant protein contacts and show that they differ significantly in terms of stability. Specifically, we show that interfaces which break readily are precisely those which are believed to form last during assembly, even though some of them might share the same contacts as other non-breaking interfaces. In particular, the interfaces that form pentamers of dimers never break, while the virtually identical interfaces within hexamers of dimers readily do. Since these units differ in the large-scale geometry and, most noticeably, the cone-angle at the center of the 5- or 6-fold vertex, we propose that the hexameric unit fails because it is pre-stressed. This not only suggests that hexamers of dimers form less frequently during the early stages of assembly; it also offers a natural explanation for the well-known β-barrel motif at the hexameric center as a post-aggregation stabilization mechanism. Finally, we identify those amino acid contacts within all key protein interfaces that are most persistent during compressive deformation of the capsid, thereby providing potential targets for mutation studies aiming to elucidate the key contacts upon which overall stability rests.

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References

  1. 1.
    F.H.C. Crick, J.D. Watson, Nature 177, 473 (1956)ADSCrossRefGoogle Scholar
  2. 2.
    V.S. Reddy, P. Natarajan, B. Okerberg, K. Li, K.V. Damodaran, R.T. Morton, C.L. Brooks, J.E. Johnson, J. Virol. 24, 11943 (2001)CrossRefGoogle Scholar
  3. 3.
    D.L.D. Casper, A. Klug, Cold Spring Harbor Symp. Quant. Biol. 27, 1 (1962)CrossRefGoogle Scholar
  4. 4.
    C.B. Frances, F.K. Thomas, J.B.W. Graheme, F.M. Edgar, D.B. Michael, R.R. John, K. Olga, S. Takehiko, T. Mitsuo, Eur. J. Biochem. 80, 319 (1977)CrossRefGoogle Scholar
  5. 5.
    P.E. Prevelige Jr., D. Thomas, J. King, Biophys. J. 3, 824 (1993)CrossRefGoogle Scholar
  6. 6.
    J.S. Stephen, R.B. Christina, P. Sreenivas, G.L. Warren, M.G. Finn, Z. Adam, Proc. Natl. Acad. Sci. 102, 8138 (2005)ADSCrossRefGoogle Scholar
  7. 7.
    J.S. Stephen, Z. Adam, J. Mol. Recognit. 19, 542 (2006)CrossRefGoogle Scholar
  8. 8.
    W. Guo-Yi, Z. Xiao-Jing, Y. Chang-Cheng, J. Dong, Z. Ling, L. Yan, W. Lai, W. Yu, C. Hong-Song, J. Chemother. 20, 458 (2008)CrossRefGoogle Scholar
  9. 9.
    S. Jingchuan, D. Chris, D. Marie-Christine, M. Ayaluru, C. Chao, G. Kodetham, S. Barry, D. Mrinmoy, M.R. Vincent, H. Andreas, Proc. Natl. Acad. Sci. 104, 1354 (2007)CrossRefGoogle Scholar
  10. 10.
    C. Chao, D. Marie-Christine, T.Q. Zachary, D. Mrinmoy, S. Barry, D.B. Valorie, R.C. Paul, M.R. Vincent, C.K. Cheng, D. Bogdan, Nano Lett. 6, 611 (2006)ADSCrossRefGoogle Scholar
  11. 11.
    J.Y. Pil, T.N. Ki, Q. Jifa, L. Soo-Kwan, P. Juhyun, M.B. Angela, H.T. Paula, Nat. Mater. 5, 234 (2006)CrossRefGoogle Scholar
  12. 12.
    Y. Ibrahim, S. Sourabh, F.S. Nicole, Curr. Opin. Biotechnol. 22, 901 (2011)CrossRefGoogle Scholar
  13. 13.
    L. LiNa, G.H. Richard, R.B. Veronica, A.L. Steven, F. Stefan, J. Am. Chem. Soc. 128, 4502 (2006)CrossRefGoogle Scholar
  14. 14.
    Y. Mark, W. Debbie, U. Masaki, D. Trevor, Annu. Rev. Phytopathol. 46, 361 (2008)CrossRefGoogle Scholar
  15. 15.
    A.A. Elizabeth, I. Steven, S.P. David, Y.W. Edwin, W.C. James, K. Kent, Nano Lett. 6, 1160 (2006)CrossRefGoogle Scholar
  16. 16.
    L. Andrew, N. Zhongwei, W. Qian, Nano Res. 2, 349 (2009)CrossRefGoogle Scholar
  17. 17.
    E.F. Christine, L. Seung-Wuk, R.P. Beau, M.B. Angela, Acta Mater. 51, 5867 (2003)CrossRefGoogle Scholar
  18. 18.
    P.P. Dustin, E.P. Peter, D. Trevor, ACS Nano 6, 5000 (2012)CrossRefGoogle Scholar
  19. 19.
    F.D. Sikkema, M. Comellas-Aragones, R.G. Fokkink, B.J.M. Verduin, J.J.L.M. Cornelissen, Org. Biomol. Chem. 5, 54 (2007)CrossRefGoogle Scholar
  20. 20.
    C.B. Chang, C.M. Knobler, W.M. Gelbart, T.G. Mason, ACS Nano 2, 281 (2008)CrossRefGoogle Scholar
  21. 21.
    M.T. Klem, D. Willits, M. Young, T. Douglas, J. Am. Chem. Soc. 125, 10806 (2003)CrossRefGoogle Scholar
  22. 22.
    P.A. Suci, M.T. Klem, F.T. Arce, T. Douglas, M. Young, Langmuir 22, 8891 (2006)CrossRefGoogle Scholar
  23. 23.
    M. Comellas-Aragones, H. Engelkamp, V.I. Claessen, N.A.J.M. Sommerdijk, A.E. Rowan, Nat. Nanotechnol. 2, 635 (2007)ADSCrossRefGoogle Scholar
  24. 24.
    E. Gillitzer, P. Suci, M. Young, T. Douglas, Small 2, 962 (2006)CrossRefGoogle Scholar
  25. 25.
    P.A. Suci, D.L. Berglund, L. Liepold, S. Brumfield, B. Pitts, Chem. Bio. 14, 387 (2007)CrossRefGoogle Scholar
  26. 26.
    P.A. Suci, Z. Varpness, E. Gillitzer, T. Douglas, M. Young, Langmuir 23, 12280 (2007)CrossRefGoogle Scholar
  27. 27.
    C.R. Kaiser, M.L. Flenniken, E. Gillitzer, A.L. Harmsen, A.G. Harmsen, Int. J. Nanomed. 2, 715 (2007)Google Scholar
  28. 28.
    Y. Ma, R.J.M. Nolte, J.J.L.M. Cornelissen, Adv. Drug Delivery Rev. 64, 811 (2012)CrossRefGoogle Scholar
  29. 29.
    G. Christoph, K. Venkatramanan, D. Markus, P. Christine, PloS one 8, e60582 (2013)CrossRefGoogle Scholar
  30. 30.
    J.P. Michel, I.L. Ivanovska, M.M. Gibbons, W.S. Klug, C.M. Knobler, G.J.L. Wuite, C.F. Schmidt, Proc. Natl. Acad. Sci. 103, 6184 (2006)ADSCrossRefGoogle Scholar
  31. 31.
    A.J. Rader, D.H. Vlad, I. Bahar, Structure 13, 413 (2005)CrossRefGoogle Scholar
  32. 32.
    F. Tama, O. Miyashita, C.L. Brooks, 3rd J. Mol. Biol. 337, 985 (2004)CrossRefGoogle Scholar
  33. 33.
    R. Konecny, J. Trylska, F. Tama, D. Zhang, N.A. Baker, Biopolymers 82, 106 (2006)CrossRefGoogle Scholar
  34. 34.
    D. Zhang, R. Konecny, N.A. Baker, J.A. McCammon, Biopolymers 75, 325 (2004)CrossRefGoogle Scholar
  35. 35.
    A. Arkhipov, P.L. Freddolino, K. Schulten, Structure 14, 1767 (2006)CrossRefGoogle Scholar
  36. 36.
    A. Arkhipov, W.H Roos, G.J.L. Wuite, K. Schulten, Biophys. J. 97, 2061 (2009)ADSCrossRefGoogle Scholar
  37. 37.
    C. Marek, O.R. Mark, J. Chem. Phys. 132, 015101 (2010)CrossRefGoogle Scholar
  38. 38.
    C. Marek, O.R. Mark, PloS one 8, e63640 (2013)CrossRefGoogle Scholar
  39. 39.
    M. Zink, H. Grubmüller, Biophys. J. 94, 1350 (2009)CrossRefGoogle Scholar
  40. 40.
    Z. Adam, A. Ryan, M. Jennifer, P.C. Johnson, J.Y. Mark, Virology 277, 450 (2000)CrossRefGoogle Scholar
  41. 41.
    E.B. Johanna, C.R.K. Heinrich, S.S. Ulrich, BMC Biophys. 5, 22 (2012)CrossRefGoogle Scholar
  42. 42.
    B. Tristan, G. Christoph, D. Markus, P. Christine, J. Chem. Theory Comput. 8, 3750 (2012)CrossRefGoogle Scholar
  43. 43.
    A.S. Jeffrey, B. Brian, Q. Chunxu, A.W. Deborah, J.Y. Mark, E.J. John, J. Virol. 80, 3582 (2006)CrossRefGoogle Scholar
  44. 44.
    J.A. Speir, S. Munshi, G. Wang, T.S. Baker, J.E. Johnson, Structure 3, 63 (1995)CrossRefGoogle Scholar
  45. 45.
    X. Zhao, J.M. Fox, N.H Olson, T.S. Baker, M.J. Young, Virology 205, 486 (1995)CrossRefGoogle Scholar
  46. 46.
    J. Tang, J.M. Johnson, K.A. Dryden, M.J. Young, A. Zlotnick, J. Struct. Biol. 154, 5967 (2006)CrossRefGoogle Scholar
  47. 47.
    R.F.K. Bruinsma, S. William, Annu. Rev. Condens. Matter Phys. 6, 245 (2015)ADSCrossRefGoogle Scholar
  48. 48.
    J.D.H. Perlmutter, F. Michael, Annu. Rev. Phys. Chem. 66, 217 (2015)ADSCrossRefGoogle Scholar
  49. 49.
    S.J. Marrink, HJ. Risselada, S. Yefimov, D.P. Tieleman, A.H. de Vries, J. Phys. Chem. B 111, 7812 (2007)CrossRefGoogle Scholar
  50. 50.
    L. Monticelli, S.K. Kandasamy, X. Periole, R.G. Larson, D.P. Tieleman, J. Chem. Theory Comput. 4, 819 (2008)CrossRefGoogle Scholar
  51. 51.
    X.C.M. Periole, SJ. Marrink, M.A. Ceruso, J. Chem. Theory Comput. 5, 2531 (2009)CrossRefGoogle Scholar
  52. 52.
    M. Seo, S. Rauscher, R. Pomes, D.P. Tieleman, J. Chem. Theory Comput. 8, 1774 (2012)CrossRefGoogle Scholar
  53. 53.
    B. Hess, C. Kutzner, D. van der Spoel, E. Lindahl, J. Chem. Theory Comput. 4, 435 (2008)CrossRefGoogle Scholar
  54. 54.
    M. Baaden, S.J. Marrink, Curr. Opin. Struct. Biol. 23, 878 (2013)CrossRefGoogle Scholar
  55. 55.
    M. del Alamo, M.G. Mateu, J. Mol. Biol. 345, 893 (2005)CrossRefGoogle Scholar
  56. 56.
    D. Chandler, Nature 437, 640 (2005)ADSCrossRefGoogle Scholar
  57. 57.
    W.K. Kegel, P. van der Schoot, Biophys. J. 91, 1501 (2006)CrossRefGoogle Scholar
  58. 58.
    W.H. Roos, M.M. Gibbons, A. Arkhipov, C. Uetrecht, N.R. Watts, P.T. Wingfield, A.C. Steven, A.J.R. Heck, K. Schulten, W.S. Klug, Biophys. J. 99, 1175 (2010)ADSCrossRefGoogle Scholar
  59. 59.
    D. Law-Hine, A.K. Sahoo, V. Bailleux, M. Zeghal, S. Prevost, P.K. Maiti, S. Bressanelli, D. Constantin, G. Tresset, J. Phys. Chem. Lett. 6, 3471 (2015)CrossRefGoogle Scholar

Copyright information

© EDP Sciences and Springer 2016

Authors and Affiliations

  • V. Krishnamani
    • 1
  • C. Globisch
    • 2
  • C. Peter
    • 2
  • M. Deserno
    • 3
    Email author
  1. 1.Department of Molecular Physiology and BiophysicsUniversity of Iowa, Carver College of MedicineIowa CityUSA
  2. 2.Department of ChemistryUniversity of Konstanz,Konstanz, Germany Max-Planck-Institute for Polymer ResearchMainzGermany
  3. 3.Department of PhysicsCarnegie Mellon UniversityPittsburghUSA

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