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WIREs Nanomed Nanobiotechnol
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Physical virology: From virus self‐assembly to particle mechanics

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Abstract Viruses are highly ordered supramolecular complexes that have evolved to propagate by hijacking the host cell's machinery. Although viruses are very diverse, spreading through cells of all kingdoms of life, they share common functions and properties. Next to the general interest in virology, fundamental viral mechanisms are of growing importance in other disciplines such as biomedicine and (bio)nanotechnology. However, in order to optimally make use of viruses and virus‐like particles, for instance as vehicle for targeted drug delivery or as building blocks in electronics, it is essential to understand their basic chemical and physical properties and characteristics. In this context, the number of studies addressing the mechanisms governing viral properties and processes has recently grown drastically. This review summarizes a specific part of these scientific achievements, particularly addressing physical virology approaches aimed to understand the self‐assembly of viruses and the mechanical properties of viral particles. Using a physicochemical perspective, we have focused on fundamental studies providing an overview of the molecular basis governing these key aspects of viral systems. This article is categorized under: Biology‐Inspired Nanomaterials > Protein and Virus‐Based Structures Nanotechnology Approaches to Biology > Nanoscale Systems in Biology
Assembly of empty particles through the nucleation, growth, and completion pathway. (a) Schematic representation of the free energy profile of the nucleation‐and‐growth/elongation pathway: first, nuclei are formed; then, the reaction proceeds downhill until the complete closure of the capsid. (Reprinted with permission from Michaels, Bellaiche, Hagan, and Knowles ()). (b) Self‐assembly model proposed for MVM empty capsids based on the sequential addition of trimeric subunits, or CBBs (capsid building blocks). (Reprinted with permission from Medrano et al. ()). (c) MVM particles imaged by TEM (left): light blue, Types I + II particles (complete capsids); green, Type I (complete capsids in basal state); magenta, Type II (complete rearranged capsids); blue, Type IIIA (large incomplete capsids); red, Type IIIB (smaller incomplete capsids). Progression of the total number of particles during disassembly (left graph) and assembly (right graph) over time. (Reprinted with permission from Medrano et al. ()). (d) CDMS spectrum in the region of 3.0 to 4.5 MDa after 2 hours (red trace) and 72 hours (black trace) from the initiation of the HBV assembly reaction with 5 μM CP dimers in 210 mM ammonium acetate. The gray shaded area shows the expected peak for the T = 4 capsids. Inset, representation of the HBV T = 4 capsid. Reprinted with permission from (Lutomski et al., ). (e) Time‐resolved CDMS spectra showing the progression of capsid assembly over the first 90 min (left) and in the scale of days (right), for an assembly reaction containing an initial CP dimer concentration of 20 μM in 510 mM ammonium acetate. (Reprinted with permission from Lutomski et al. ()). CBB, capsid building block; CDMS, charge detection mass spectrometry; CP, capsid protein; MVM, minute virus of mice; TEM, transmission electron microscopy
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Mechanical fatigue of human adenovirus immature (IC), mature Ad5 (WT), and G33 mutant (G33) capsids. (a) Schematic representation of IC, WT, and G33 particles with relevant core component composition. (b) Plot of change in height over time for constant AFM imaging of WT particles. Inset: first derivative of sigmoidal fit from the plot in (b). (c) Plot of change in volume over imaging time for IC particles. Inset: first derivative of sigmoidal fit of curves in main panel. (d) Comparative representation of cumulative percentage of penton release of WT and G33 particles for AFM tip induced fatigue experiments. (Reproduced from Denning et al. () with permission from The Royal Society of Chemistry). AFM, atomic force microscopy
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Effect of genome encapsulation and maturation. (a) Force–indentation curves obtained from an empty particle, a prohead and a complete virion of the φ29 bacteriophage. Inset is a typical AFM image of a φ29 bacteriophage virion, with a superimposed reconstruction from EM. (b) Calculated spring constant from the experiments in (a). (Panel a and b taken from Hernando‐Perez et al. (), with permission from the publisher). (c) Scheme of in vivo maturation of bacteriophage P22. (d) P22 VLP reconstructions at different stages. (e) The measured spring constant (left) and height (right) of capsids in different stages. PC: procapsid, ES: empty capsid, EX: expanded shell for five‐, three‐, and twofold symmetry (S5, S3, and S2, respectively). (Panels taken from Kant et al. (); with permission from the publishers). AFM, atomic force microscopy
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Response of virus particles to indentation forces. (a) Scheme of AFM nanoindentation experiment. (b–d) Examples of particles showing different effects upon indentation. (b) Mechanical failure of picorna‐like Triatoma virus (TrV). (Panels adjusted from Snijder et al. (2013); with permission from the publisher). (c) Irreversible deformation of herpes simplex virus Type 1 (HSV1). (Panels adjusted from Klug et al. (); with permission from the publisher). (d) Reversible deformation of T7 bacteriophage. The particle shows plastic deformation immediate after the indentation, but resumed its structure after ∼36 min (right panel). (Panels adapted from de Pablo et al. (); with permission from the publisher). AFM, atomic force microscopy
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Contributions of RNA topology to viral assembly. (a) Comparison of the secondary structure of BMV RNA (left structure), and a nonviral random RNA sequence (right structure) with equal numbers of bases and base proportions. The maximum ladder distance, that is, the number of basepairs crossed along the trajectory between the two most distant hairpin loops, of both structures are 207 and 354, respectively, represented as red lines. (Reprinted with permission from Ben‐Shaul and Gelbart ()). (b) Plot of the charge ratios (genome charge/CP charge) calculated for several viruses (green pentagons), and predicted for linear polyelectrolytes (red circles) and model nucleic acids with 50% base‐pairing (blue triangles). (Reprinted with permission from Perlmutter et al. ()). (c) Size distributions of the VLPs formed from competitive self‐assembly. Left, competition assay in which polyU (~22 nm peak) and BMV RNA (28 nm peak) are mixed simultaneously. Right, competition assays altering the order of addition of polyU and B1 (BMV RNA). (Reprinted with permission from Beren, Dreesens, Liu, Knobler, and Gelbart ()). (d) Free energy of encapsidation for linear and branched polynucleotides as a function of chain size. Left, effect of stiffness and charge density. Right, a closer look at the changes in charge density. Parameters are l (Kuhn length), τ (charge within one Kuhn segment), and fb (fugacity). (Reprinted with permission from Li, Erdemci‐Tandogan, van der Schoot, and Zandi ()). BMV, Brome mosaic virus; CP, capsid protein; VLP, virus‐like particle
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MS2 assembly predicted by the PS‐mediated model. (a) Representation of the MS2 genome with the 15 stem‐loops (magenta boxes) found in the asymmetric cryo‐EM reconstruction (Dai et al., ), and previously predicted to be PSs via HPA (Dykeman, Stockley, & Twarock, 2013). (b) Hamiltonian path representation of MS2 genome arrangement connecting binding sites inside the MS2 capsid. (a and b reprinted with permission from Twarock, Leonov, and Stockley ()). (c) Left, identified PSs by cryo‐EM reconstruction of MS2 particles at 8.7 Å resolution (Koning et al., ) are predominantly located in one half of the capsid; in agreement with predictions (right; Dykeman et al., 2013), showing that the positions of PSs bound to CPs (red rhombs) are also mainly located in one half of the capsid inner surface. (c reprinted with permission from Twarock, Bingham, et al. ()). CP, capsid protein; HPA, Hamiltonian path analysis; PS, packaging signal
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Energetics of the self‐assembly of genome‐filled capsids. (a) Snapshots obtained from simulations of the nucleation‐and‐growth (ordered) and en masse (disordered) assembly pathways by tuning the parameters εSS (protein–protein interaction strength) and I (ionic strength). (Reprinted with permission from Perlmutter et al. ()). (b) Free energy landscape scheme of CCMV assembly modulated by the change in ionic strength (left) and pH (right). Left, the graph shows the formation of a CP‐genome amorphous complex through the en masse pathway, driven by CP–genome interactions. Right, the amorphous complex rearranges into a full capsid by the increased strength of CP–CP interactions through the synchronous pathway. Dark colors delimit areas of low free energy, while light colors represent high free energies regions. (Reprinted with permission from Chevreuil et al. ()). CCMV, Cowpea chlorotic mottle virus; CP, capsid protein
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