Abstract
Viruses are nanosized, genome-filled protein containers with remarkable thermodynamic and mechanical properties. They form by spontaneous self-assembly inside the crowded, heterogeneous cytoplasm of infected cells. Self-assembly of viruses seems to obey the principles of thermodynamically reversible self-assembly but assembled shells (‘capsids’) strongly resist disassembly. Following assembly, some viral shells pass through a sequence of coordinated maturation steps that progressively strengthen the capsid. Nanoindentation measurements by atomic force microscopy enable tests of the strength of individual viral capsids. They show that concepts borrowed from macroscopic materials science are surprisingly relevant to viral shells. For example, viral shells exhibit ‘materials fatigue’ and the theory of thin-shell elasticity can account — in part — for atomic-force-microscopy-measured force–deformation curves. Viral shells have effective Young’s moduli ranging from that of polyethylene to that of plexiglas. Some of them can withstand internal osmotic pressures that are tens of atmospheres. Comparisons with thin-shell theory also shed light on nonlinear irreversible processes such as plastic deformation and failure. Finally, atomic force microscopy experiments can quantify the mechanical effects of genome encapsidation and capsid protein mutations on viral shells, providing virological insight and suggesting new biotechnological applications.
This is a preview of subscription content, access via your institution
Access options
Subscribe to this journal
Receive 12 print issues and online access
$209.00 per year
only $17.42 per issue
Rent or buy this article
Prices vary by article type
from$1.95
to$39.95
Prices may be subject to local taxes which are calculated during checkout
Similar content being viewed by others
Change history
02 November 2010
In the HTML version of this Review originally published, the two figures in Box 2 were inadvertantly switched; this has now been corrected.
References
Fischlechner, M. & Donath, E. Viruses as building blocks for materials and devices. Angew. Chem. Int. Ed. 46, 3184–3193 (2007).
Singh, P., Gonzalez, M. J. & Manchester, M. Viruses and their uses in nanotechnology. Drug Dev. Res. 67, 23–41 (2006).
Lee, Y. J. et al. Fabricating genetically engineered high-power lithium-ion batteries using multiple virus genes. Science 324, 1051–1055 (2009).
Tseng, R. J., Tsai, C. L., Ma, L. P. & Ouyang, J. Y. Digital memory device based on tobacco mosaic virus conjugated with nanoparticles. Nature Nanotechnol. 1, 72–77 (2006).
Everts, M. et al. Covalently linked Au nanoparticles to a viral vector: Potential for combined photothermal and gene cancer therapy. Nano Lett. 6, 587–591 (2006).
Douglas, T. & Young, M. Host–guest encapsulation of materials by assembled virus protein cages. Nature 393, 152–155 (1998).
Parato, K. A., Senger, D., Forsyth, P. A. J. & Bell, J. C. Recent progress in the battle between oncolytic viruses and tumours. Nature Rev. Cancer 5, 965–976 (2005).
Kay, M. A., Glorioso, J. C. & Naldini, L. Viral vectors for gene therapy: The art of turning infectious agents into vehicles of therapeutics. Nature Med. 7, 33–40 (2001).
Summers, W. C. Bacteriophage therapy. Annu. Rev. Microbiol. 55, 437–451 (2001).
Stockley, P. & Twarock, R. (eds) Emerging Topics in Physical Virology (Imperial College, 2010).
Bruinsma, R. F., Gelbart, W. M., Reguera, D., Rudnick, J. & Zandi, R. Viral self-assembly as a thermodynamic process. Phys. Rev. Lett. 90, 248101 (2003).
Zlotnick, A. Theoretical aspects of virus capsid assembly. J. Mol. Recognit. 18, 479–490 (2005).
Gelbart, W. M. & Knobler, C. M. Pressurized viruses. Science 323, 1682–1683 (2009).
Roos, W. H., Ivanovska, I. L., Evilevitch, A. & Wuite, G. J. L. Viral capsids: Mechanical characteristics, genome packaging and delivery mechanisms. Cell. Mol. Life Sci. 64, 1484–1497 (2007).
Sun, S. Y., Rao, V. B. & Rossmann, M. G. Genome packaging in viruses. Curr. Opin. Struct. Biol. 20, 114–120 (2010).
Baumeister, W. & Steven, A. C. Macromolecular electron microscopy in the era of structural genomics. Trends Biochem. Sci. 25, 624–631 (2000).
Natarajan, P. et al. Exploring icosahedral virus structures with VIPER. Nature Rev. Microbiol. 3, 809–817 (2005).
Fraenkel-Conrat, H. & Williams, R. C. Reconstitution of active tobacco mosaic virus from its inactive protein and nucleic acid components. Proc. Natl Acad. Sci. USA 41, 690–698 (1955).
Butler, P. J. G. & Klug, A. Assembly of a virus. Sci. Am. 239, 62–69 (1978).
Bancroft, J. B., Hills, G. J. & Markham, R. A study of self-assembly process in a small spherical virus—formation of organized structures from protein subunits in vitro. Virology 31, 354–379 (1967).
Klug, A. The tobacco mosaic virus particle: Structure and assembly. Phil. Trans. R. Soc. Lond. B 354, 531–535 (1999).
Caspar, D. L. D. Assembly and stability of the tobacco mosaic virus particle. Adv. Protein Chem. 18, 37–121 (1963).
Kegel, W. K. & van der Schoot, P. Physical regulation of the self-assembly of tobacco mosaic virus coat protein. Biophys. J. 91, 1501–1512 (2006).
Bruinsma, R. F. Physics of RNA and viral assembly. Eur. Phys. J. E 19, 303–310 (2006).
Tang, L. et al. The structure of Pariacoto virus reveals a dodecahedral cage of duplex RNA. Nature Struct. Biol. 8, 77–83 (2001).
Johnson, J. M. et al. Regulating self-assembly of spherical oligomers. Nano Lett. 5, 765–770 (2005).
Ceres, P. & Zlotnick, A. Weak protein–protein interactions are sufficient to drive assembly of hepatitis B virus capsids. Biochemistry 41, 11525–11531 (2002).
Safran, S. Statistical Thermodynamics of Surfaces, Interfaces, and Membranes; Frontiers in Physics (Westview Press, 2003).
Singh, S. & Zlotnick, A. Observed hysteresis of virus capsid disassembly is implicit in kinetic models of assembly. J. Biol. Chem. 278, 18249–18255 (2003).
Morozov, A. Y., Bruinsma, R. F. & Rudnick, J. Assembly of viruses and the pseudo-law of mass action. J. Chem. Phys. 131, 155101 (2009).
Endres, D. & Zlotnick, A. Model-based analysis of assembly kinetics for virus capsids or other spherical polymers. Biophys. J. 83, 1217–1230 (2002).
Berthet-Colominas, C., Cuillel, M., Koch, M. H. J., Vachette, P. & Jacrot, B. Kinetic-study of the self-assembly of brome mosaic-virus capsid. Eur. Biophys. J. Biophys. Lett. 15, 159–168 (1987).
Prevelige, P. E., Thomas, D. & King, J. Nucleation and growth phases in the polymerization of coat and scaffolding subunits into icosahedral procapsid shells. Biophys. J. 64, 824–835 (1993).
Choi, Y. G., Dreher, T. W. & Rao, A. L. N. tRNA elements mediate the assembly of an icosahedral RNA virus. Proc. Natl Acad. Sci. USA 99, 655–660 (2002).
Zlotnick, A., Aldrich, R., Johnson, J. M., Ceres, P. & Young, M. J. Mechanism of capsid assembly for an icosahedral plant virus. Virology 277, 450–456 (2000).
Casini, G. L., Graham, D., Heine, D., Garcea, R. L. & Wu, D. T. In vitro papillomavirus capsid assembly analyzed by light scattering. Virology 325, 320–327 (2004).
Nguyen, T. T., Bruinsma, R. F. & Gelbart, W. M. Continuum theory of retroviral capsids. Phys. Rev. Lett. 96, 078102 (2006).
Endres, D., Miyahara, M., Moisant, P. & Zlotnick, A. A reaction landscape identifies the intermediates critical for self-assembly of virus capsids and other polyhedral structures. Protein Sci. 14, 1518–1525 (2005).
Zhang, T. Q. & Schwartz, R. Simulation study of the contribution of oligomer/oligomer binding to capsid assembly kinetics. Biophys. J. 90, 57–64 (2006).
Hemberg, M., Yaliraki, S. N. & Barahona, M. Stochastic kinetics of viral capsid assembly based on detailed protein structures. Biophys. J. 90, 3029–3042 (2006).
Hagan, M. F. & Chandler, D. Dynamic pathways for viral capsid assembly. Biophys. J. 91, 42–54 (2006).
Hicks, S. D. & Henley, C. L. Irreversible growth model for virus capsid assembly. Phys. Rev. E 74, 031912 (2006).
Nguyen, H. D., Reddy, V. S. & Brooks, C. L. Invariant polymorphism in virus capsid assembly. J. Am. Chem. Soc. 131, 2606–2614 (2009).
Rapaport, D. C. Role of reversibility in viral capsid growth: A paradigm for self-assembly. Phys. Rev. Lett. 101, 186101 (2008).
Berger, B., Shor, P. W., Tuckerkellogg, L. & King, J. Local rule-based theory of virus shell assembly. Proc. Natl Acad. Sci. USA 91, 7732–7736 (1994).
Zandi, R., Reguera, D., Bruinsma, R. F., Gelbart, W. M. & Rudnick, J. Origin of icosahedral symmetry in viruses. Proc. Natl Acad. Sci. USA 101, 15556–15560 (2004).
Chen, T., Zhang, Z. L. & Glotzer, S. C. A precise packing sequence for self-assembled convex structures. Proc. Natl Acad. Sci. USA 104, 717–722 (2007).
Nguyen, T. T., Bruinsma, R. F. & Gelbart, W. M. Elasticity theory and shape transitions of viral shells. Phys. Rev. E 72, 051923 (2005).
Moody, M. F. Geometry of phage head construction. J. Mol. Biol. 293, 401–433 (1999).
Chen, T. & Glotzer, S. C. Simulation studies of a phenomenological model for elongated virus capsid formation. Phys. Rev. E 75, 051504 (2007).
Luque, A., Zandi, R. & Reguera, D. Optimal architectures of elongated viruses. Proc. Natl Acad. Sci. USA 107, 5323–5328 (2010).
Zhang, R. & Nguyen, T. T. Model of human immunodeficiency virus budding and self-assembly: Role of the cell membrane. Phys. Rev. E 78, 051903 (2008).
Guerin, T. & Bruinsma, R. Theory of conformational transitions of viral shells. Phys. Rev. E 76, 061911 (2007).
Wikoff, W. R. et al. Topologically linked protein rings in the bacteriophage HK97 capsid. Science 289, 2129–2133 (2000).
Tama, F. & Brooks, C. L. The mechanism and pathway of pH induced swelling in cowpea chlorotic mottle virus. J. Mol. Biol. 318, 733–747 (2002).
Tama, F. & Brooks, C. L. Diversity and identity of mechanical properties of icosahedral viral capsids studied with elastic network normal mode analysis. J. Mol. Biol. 345, 299–314 (2005).
Widom, M., Lidmar, J. & Nelson, D. R. Soft modes near the buckling transition of icosahedral shells. Phys. Rev. E 76, 031911 (2007).
Yang, Z., Bahar, I. & Widom, M. Vibrational dynamics of icosahedrally symmetric biomolecular assemblies compared with predictions based on continuum elasticity. Biophys. J. 96, 4438–4448 (2009).
Anderson, T. F., Rappaport, C. & Muscatine, N. A. On the structure and osmotic properties of phage particles. Ann. Inst. Pasteur 84, 5–15 (1953).
Stephanidis, B., Adichtchev, S., Gouet, P., McPherson, A. & Mermet, A. Elastic properties of viruses. Biophys. J. 93, 1354–1359 (2007).
Hartschuh, R. D. et al. How rigid are viruses. Phys. Rev. E 78, 021907 (2008).
Smith, D. E. et al. The bacteriophage phi 29 portal motor can package DNA against a large internal force. Nature 413, 748–752 (2001).
Evilevitch, A., Lavelle, L., Knobler, C. M., Raspaud, E. & Gelbart, W. M. Osmotic pressure inhibition of DNA ejection from phage. Proc. Natl Acad. Sci. USA 100, 9292–9295 (2003).
Lidmar, J., Mirny, L. & Nelson, D. R. Virus shapes and buckling transitions in spherical shells. Phys. Rev. E 68, 051910 (2003).
Roos, W. H. et al. Scaffold expulsion and genome packaging trigger stabilization of herpes simplex virus capsids. Proc. Natl Acad. Sci. USA 106, 9673–9678 (2009).
Liashkovich, I. et al. Exceptional mechanical and structural stability of HSV-1 unveiled with fluid atomic force microscopy. J. Cell Sci. 121, 2287–2292 (2008).
Ivanovska, I. L. et al. Bacteriophage capsids: Tough nanoshells with complex elastic properties. Proc. Natl Acad. Sci. USA 101, 7600–7605 (2004).
Carrasco, C. et al. DNA-mediated anisotropic mechanical reinforcement of a virus. Proc. Natl Acad. Sci. USA 103, 13706–13711 (2006).
Zhao, Y., Ge, Z. B. & Fang, J. Y. Elastic modulus of viral nanotubes. Phys. Rev. E 78, 031914 (2008).
Gibbons, M. M. & Klug, W. S. Nonlinear finite-element analysis of nanoindentation of viral capsids. Phys. Rev. E 75, 031901 (2007).
Michel, J. P. et al. Nanoindentation studies of full and empty viral capsids and the effects of capsid protein mutations on elasticity and strength. Proc. Natl Acad. Sci. USA 103, 6184–6189 (2006).
Gibbons, M. M. & Klug, W. S. Influence of nonuniform geometry on nanoindentation of viral capsids. Biophys. J. 95, 3640–3649 (2008).
Roos, W. H. et al. Squeezing protein shells: how continuum elastic models, molecular dynamics simulations and experiments coalesce at the nanoscale. Biophys. J. 99, 1175–1181 (2010).
Uetrecht, C. et al. High-resolution mass spectrometry of viral assemblies: Molecular composition and stability of dimorphic hepatitis B virus capsids. Proc. Natl Acad. Sci. USA 105, 9216–9220 (2008).
Carrasco, C., Castellanos, M., de Pablo, P. J. & Mateu, M. G. Manipulation of the mechanical properties of a virus by protein engineering. Proc. Natl Acad. Sci. USA 105, 4150–4155 (2008).
Ivanovska, I., Wuite, G., Jonsson, B. & Evilevitch, A. Internal DNA pressure modifies stability of WT phage. Proc. Natl Acad. Sci. USA 104, 9603–9608 (2007).
Klug, W. S. et al. Failure of viral shells. Phys. Rev. Lett. 97, 228101 (2006).
Evans, E. & Ritchie, K. Dynamic strength of molecular adhesion bonds. Biophys. J. 72, 1541–1555 (1997).
Roos, W. H. & Wuite, G. J. L. Nanoindentation studies reveal material properties of viruses. Adv. Mater. 21, 1187–1192 (2009).
Arkhipov, A., Roos, W. H., Wuite, G. J. & Schulten, K. Elucidating the mechanism behind irreversible deformation of viral capsids. Biophys. J. 97, 2061–2069 (2009).
Freddolino, P. L., Arkhipov, A. S., Larson, S. B., McPherson, A. & Schulten, K. Molecular dynamics simulations of the complete satellite tobacco mosaic virus. Structure 14, 437–449 (2006).
Arkhipov, A., Freddolino, P. L. & Schulten, K. Stability and dynamics of virus capsids described by coarse-grained modeling. Structure 14, 1767–1777 (2006).
Zink, M. & Grubmuller, H. Mechanical properties of the icosahedral shell of southern bean mosaic virus: A molecular dynamics study. Biophys. J. 96, 1350–1363 (2009).
Cieplak, M. & Robbins, M. O. Nanoindentation of virus capsids in a molecular model. J. Chem. Phys. 132, 015101 (2010).
Landau, L. D. & Lifshitz, E. M. Theory of Elasticity 3rd edn (Elsevier, 1986).
Morozov, A., Rudnick, J., Bruinsma, R. & Klug, W. in Emerging Topics in Physical Virology (eds Stockley, P. & Twarock, R.) (Imperial College, 2010).
Baker, M. L., Jiang, W., Rixon, F. J. & Chiu, W. Common ancestry of herpesviruses and tailed DNA bacteriophages. J. Virol. 79, 14967–14970 (2005).
Kol, N. et al. Mechanical properties of murine leukemia virus particles: Effect of maturation. Biophys. J. 91, 767–774 (2006).
Kol, N. et al. A stiffness switch in human immunodeficiency virus. Biophys. J. 92, 1777–1783 (2007).
Newcomb, W. W. & Brown, J. C. Structure of the herpes-simplex virus capsid—effects of extraction with guanidine-hydrochloride and partial reconstitution of extracted capsids. J. Virol. 65, 613–620 (1991).
Li, Y. Y. et al. Control of virus assembly: HK97 ‘Whiffleball’ mutant capsids without pentons. J. Mol. Biol. 348, 167–182 (2005).
Zlotnick, A. Viruses and the physics of soft condensed matter. Proc. Natl Acad. Sci. USA 101, 15549–15550 (2004).
Caspar, D. L. D. & Klug, A. Physical principles in construction of regular viruses. Cold Spring Harbor Symp. Quant. Biol. 27, 1–24 (1962).
Johnson, J. E. & Speir, J. A. Quasi-equivalent viruses: A paradigm for protein assemblies. J. Mol. Biol. 269, 665–675 (1997).
Crick, F. H. C. & Watson, J. D. Structure of small viruses. Nature 177, 473–475 (1956).
Kasas, S. & Dietler, G. Probing nanomechanical properties from biomolecules to living cells. Pflugers Arch. 456, 13–27 (2008).
Radmacher, M., Fritz, M., Kacher, C. M., Cleveland, J. P. & Hansma, P. K. Measuring the viscoelastic properties of human platelets with the atomic force microscope. Biophys. J. 70, 556–567 (1996).
Sen, S., Subramanian, S. & Discher, D. E. Indentation and adhesive probing of a cell membrane with AFM: Theoretical model and experiments. Biophys. J. 89, 3203–3213 (2005).
Vinckier, A., Dumortier, C., Engelborghs, Y. & Hellemans, L. Dynamical and mechanical study of immobilized microtubules with atomic force microscopy. J. Vac. Sci. Technol. B 14, 1427–1431 (1996).
de Pablo, P. J., Schaap, I. A. T., MacKintosh, F. C. & Schmidt, C. F. Deformation and collapse of microtubules on the nanometer scale. Phys. Rev. Lett. 91, 098101 (2003).
Kol, N. et al. Self-assembled peptide nanotubes are uniquely rigid bioinspired supramolecular structures. Nano Lett. 5, 1343–1346 (2005).
Kuznetsov, Y. G., Malkin, A. J., Lucas, R. W., Plomp, M. & McPherson, A. Imaging of viruses by atomic force microscopy. J. Gen. Virol. 82, 2025–2034 (2001).
Baclayon, M., Wuite, G. J. L. & Roos, W. H. Imaging and manipulation of single viruses by atomic force microscopy. Soft Matterdoi:10.1039/b923992h (2010, in the press).
Putman, C. A. J., Vanderwerf, K. O., Degrooth, B. G., Vanhulst, N. F. & Greve, J. Tapping mode atomic-force microscopy in liquid. Appl. Phys. Lett. 64, 2454–2456 (1994).
Moreno-Herrero, F. et al. Scanning force microscopy jumping and tapping modes in liquids. Appl. Phys. Lett. 81, 2620–2622 (2002).
Acknowledgements
G.J.L.W. would like to acknowledge support by the Nederlandse Organisatie voor Wetenschappelijk Onderzoek in a CW-ECHO and a VICI grant, and support by the Stichting voor Fundamenteel Onderzoek der Materie under the ‘Physics of the genome’ research programme. R.B. would like to thank the NSF-DMR for support under Grant 0704274.
Author information
Authors and Affiliations
Corresponding authors
Ethics declarations
Competing interests
The authors declare no competing financial interests.
Rights and permissions
About this article
Cite this article
Roos, W., Bruinsma, R. & Wuite, G. Physical virology. Nature Phys 6, 733–743 (2010). https://doi.org/10.1038/nphys1797
Received:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1038/nphys1797
This article is cited by
-
Physical virology: how physics is enabling a better understanding of recent viral invaders
Biophysical Reviews (2023)
-
Freestanding non-covalent thin films of the propeller-shaped polycyclic aromatic hydrocarbon decacyclene
Nature Communications (2022)
-
Thermoresponsive C22 phage stiffness modulates the phage infectivity
Scientific Reports (2022)
-
Physics of viral dynamics
Nature Reviews Physics (2021)
-
Morphology selection kinetics of crystallization in a sphere
Nature Physics (2021)