Virus-Based Devices: Prospects for Allopoiesis Bogdan Dragnea* Department of Chemistry, Indiana University, Bloomington, Indiana 47405, United States ABSTRACT: The assembly line is a commonly invoked example of allopoiesis, the process whereby a system produces a different system than itself. In this sense, virus production in plants is an instance of bio-enabled bottom-up allopoiesis because the plant host can be regarded as a programmable assembly line for the virus. Reprogramming this assembly line and integrating it into a larger lineup of chemical manipulations has seen a flurry of activity recently, with more sophisticated systems emerging every year. The field of virus nanomaterials now has several subdisciplines that focus on virus shells as assemblers, scaffolds for molecular circuitry, chemical reactors, magnetic and photonic beacons, and therapeutic carriers. A case in point is the work reported by Brillault et al. in this issue of ACS Nano. They show how two types of animal virus coat proteins can be simultaneously expressed and efficiently assembled in plants into a complex virus-like particle of well-defined stoichiometry and composition. Such advances, combined with the promise of scalability and sustainability afforded by plants, paint a bright picture for the future of high-performance virus-based nanomaterials.
C
Another factor is the resilience of certain plant viruses, including TMV, to challenges associated with ex vivo environments. J. D. Bernal noted in his 1940s studies of TMV gels by X-ray diffraction that the most striking feature of the intramolecular diffraction pattern in TMV was its insensitivity to the state of hydration.4 Scalability and resilience are still properties of interest today, especially for the emerging field of virusdirected nanofabrication;5,6 one example is TMV-assisted nanofabrication of coatings for enhanced boiling.7 It is reasonable to hypothesize that there might be some correlation between the pathways of virus spread and the degree of resilience to chemical manipulation. To move from host to host, plant viruses must drastically change environments, perhaps more so than animal viruses. Some rely on vectorsherbivorous insects, for instance. Others, such as the tomato mosaic virus (ToMV), which belongs to the alphaviruslike superfamily of (+)RNA viruses that also includes TMV, have no recognized vector. The persistence of viable ToMV particles for long periods of time in a variety of environments, from soil to cloud droplets, is key to their ability to spread.8 What are the mechanisms by which ToMV achieves such resilience to harsh environments? Could this property lead to labile molecule storage technologies or bottom-up lattices and networks of biomolecular components resistant to dehydration? The first infectious virus to be reconstituted in vitro from purified protein and nucleic acid components was TMV.9 The first in vitro spherical virus to be reconstituted was another plant virus, the cowpea chlorotic mottle virus (CCMV).10 In vitro reconstitution of virus particles confirmed that the RNA isolated from virus samples is the genetic material (which was not clear at the time) and also that plant viruses such as TMV
hemical manipulation of viruses has a venerable history within molecular biology but has recently cut across disparate fields of science. In this Perspective, I lay out a broader context for the contributions of Brillault et al. detailed in this issue of ACS Nano1 by describing the state of the field for an area in physical sciences where viruses are molecular self-assemblers and enablers of chemical nanoreactors, highperformance beacons, carriers, and molecular circuit scaffolds. The first known chemical manipulations of a virus are attributed to Martinus Beijerinck, at the turn of the 20th cenury.2 Beijerinck showed that alcoholic precipitation would leave the active principle of tobacco mosaic disease intact. In 1929, Vinson and Petre succeeded in purifying the agent of tobacco mosaic disease, showing that it could be subjected to several kinds of chemical manipulations without loss of activity, and even obtained crystals by concentrating the agent.3 The agent was a plant virus, and its crystallization is seen as the symbolic moment for the beginning of molecular biology. In his 1946 Nobel lecture, Wendell Stanley noted: “The fact that, with respect to size, the viruses overlapped with the organisms of the biologist at one extreme and with the molecules of the chemist at the other extreme only served to heighten the mystery regarding the nature of viruses.” Seventy years later, the mystery continues to unravel in surprising directions at the chemical end of the spectrum. Remaining for a moment within the realm of history, it is interesting to note that crystals of many other plant viruses were obtained soon after Vinson, Petre, and Stanley reported their findings on tobacco mosaic virus (TMV), but crystallization of the first animal virus did not occur until 20 years later. Several factors may be responsible for this time lag and resulting early plant virus dominance in the nascent field of molecular virology. One factor is the large amount of highly infectious starting material that is obtainable from plants. © 2017 American Chemical Society
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transformations between states with the same symmetry but different volumes in response to environmental cues. The ability of CCMV to swell reversibly was utilized by Douglas and Young, and many other groups since, in seminal work on host−guest encapsulation (see Figure 1A).16 Studies of macroscopic mechanical analogues, termed expandohedra, led to the conjecture that only odd T numbers may support a fully symmetric swelling motion (see Figure 1B).17 This example illustrates how a design principle for virusmimicking capsules with reversible transitions can be borne out from cross-fertilization of seemingly disparate disciplines. Stanley’s comment about viruses being situated on the boundary between chemistry and biology extends to mechanics and even farther today. This extension is perhaps not surprising since typical dimensions relevant to viruses cover a range uniquely characterized by a confluence of energy scales for thermal, chemical, mechanical, and electrostatic interactions. At the virus scale, coupling may occur between degrees of freedom that at any other scale could be safely considered to be independent.18 Assembly. Although icosahedral viruses can take T numbers between 1 and ∼1200, for applications that necessitate varying the size of the cage, it would be impractical to change the virus every time a new size is required. Therefore, questions of interest include how can we control triangulation numbers in virus-like particles (VLPs) and what price is there to pay for straying away from what nature provides? To answer these questions, a detailed understanding of the driving forces responsible for assembly and stability of the final thermodynamic state is necessary. There is already a large body of simulation and theoretical studies dedicated to these topics.19,20 However, systematic experiments that paint reasonably detailed energy landscapes and follow trajectories in time are lagging. For instance, although qualitative predictions of free energy as a function of the number of capsomers were made more than a decade ago,21 no experimental counterpart exists at this point. However, qualitative steps in this direction have been made. For instance, genetic manipulation of CCMV has shed light on how polymorphism may be achieved. In CCMV, the coat protein is structured according to one of the two canonical motifs encountered in icosahedral viruses.22 A rigid, β-barrel domain is responsible for capsid tiling, whereas a flexible, arginine-rich, N-terminal domain oriented toward the lumenal cavity is responsible for interaction with the RNA. This interaction is predominantly electrostatic, although specific interactions are believed to add to it. In vitro, in the absence of nucleic acid, and at high salt, T = 3 empty capsids form from CCMV coat proteins alone, due to
Understanding the mechanisms behind quality control during virus assembly remains one of the greatest challenges of physical virology. or CCMV spontaneously assemble from free coat protein and RNA components to reach a thermodynamically stable state, which corresponds to a biologically functional particle, or virion. Furthermore, whereas proteins alone aggregated in a variety of complexes, nucleoprotein particles, which form by co-assembly of viral RNA and coat protein, were remarkably monodisperse, indeed identical at every scale. In contrast with most artificial self-assembling materials, virus assembly is often self-controlled;11 that is, a large variety of virus components contain instructions for quality check and self-termination and, consequently, for attainment of tight stoichiometric precision. Understanding the mechanisms behind quality control during virus assembly remains one of the greatest challenges of physical virology. In many virus shells, symmetry arises akin to crystallization, from packing of identical monomers. Having a small number of monomer types offers the biological benefit of genome economy.12 The majority of isometric viruses adopt icosahedral symmetry, the icosahedron being the regular polyhedron with the largest volume-to-surface ratio. Their shells contain 60 T protein subunits, where the triangulation number, T, follows the series: T = h2 + hk + k2, with h, k, integers. Shells of lower symmetry such as those of spherocylindrical and rod-like viruses exist as well and point to different potential functional advantages that overcome those associated with icosahedral symmetry. For instance, higher aspect ratio virus-based delivery vectors have been proposed to hold the benefits of enhanced margination toward blood vessel walls, increased transport across tissue membranes, and reduced clearance by phagocytosis.13,14 Symmetry. Function closely relates to symmetry. Thus, symmetry (or the lack thereof) will affect equilibrium properties, such as the arrangement of chemically addressable groups in biotemplating, thermodynamic stability, and the connectivity of extended lattices of interacting engineered virus particles. Symmetry may also constrain dynamics, as stress fields born out of geometric frustration may favor certain transition pathways over others in navigating among the structures that make the maturation process.15 An interesting related phenomenon is encountered in a number of icosahedral plant viruses, which are known to undergo
Figure 1. (A) T = 3 capsid of cowpea chlorotic mottle virus can transition reversibly between a compact and a swollen form in different buffer conditions. Adapted with permission from ref 16. Copyright 1998 Macmillan Publishers Ltd. (B) States of a mechanical analogue based on the cube. Adapted with permission from ref 17. Copyright 2004 The Royal Society. 3434
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the screening of repulsive N-termini interactions and dominance of attractive interactions between β-barrel domains.23 A mutant of the coat protein that lacked most of the N-terminus assembled in vitro into statistically predictable numbers of native-like T = 3 capsids, pseudo-T = 2 capsids, and T = 1 capsid having diameters of 290, 250, and 180 Å, respectively.24 These findings suggest that there is flexibility of the dihedral angle between capsomers in CCMV, which enables multiple triangulations of the icosahedron to be metastable. Figure 2 shows a two-dimensional (2D) graphic representation of a possible polymorphism scenario. In this model, there
Figure 3. Schematic showing chains of mutant subunits lacking the N-terminus, with constitutive interactions occurring at two mutually exclusive binding interfaces. The structures are organized qualitatively according energy and number of subunits and labeled according the number of interfaces of each type (NS, NL).
Figure 2. (A) Graphic representation of a typical coat protein subunit, having a bulky rigid domain characterized by a hinge region and two binding surfaces, L and S, which form angles of θL/ 2 and θS/2 with the subunit symmetry axis, respectively (also see Figure 3, inset). In this example, the angles were chosen so that their ratio is a rational number: θL = π/6, θS = π/3, which ensures that it is possible to form two circular chains each containing a single type of binding. (B) Circular chain homogeneously bound by S interfaces. (C) Circular chain homogeneously bound by L interfaces.
different from other molecular assembly processes of biological inspiration, which boast similar figures of merit in terms of specificity, scale, and accuracy. For instance, structural DNA nanotechnology has superb design control for accessing a variety of target shapes and functions26 but much slower kinetics than virus growth for similarly complex architectures. This difference is perhaps not surprising since viruses are under evolutionary pressure to enclose their genomes in a protective shell without delay upon replication. How this enclosure is achieved, exactly, remains unclear for most viruses. Much work remains in developing analytical methods that are capable of following the dynamics of the virus-assembly process, especially methods that can avoid averaging among intermediates. The simple 2D assembly model inspired by CCMV also highlights how deeply the interactions at the lumenal interface may influence the assembly outcome. This potential influence is worth considering when loading foreign cargo or when modifying one of the virus interfaces chemically or genetically, like in the Brillault et al. article.1 A dramatic example comes from experiments with nanoparticle encapsulation in shells formed from a close relative of CCMV, the brome mosaic virus.27 Even when working with intact coat proteins, it is possible to induce any of the three capsid polymorphs (T = 1, pseudo-T = 2, and T = 3) selectively to become the most stable state, by tuning the nanoparticle template radius to match that of a closed shell and by lowering the total energy associated with a selected T number through electrostatic interactions between the ligand coat of the nanoparticle core and the basic residues of the coat protein N-terminus.
is no single spontaneous curvature for the coat protein subunit: the subunit shape enables two possible angles between the symmetry axes of adjacent subunits, corresponding to two contact areas. For any other angles, the contact area is zero. Assuming interactions are independent of size, the Helmholtz free energy for a chain containing NL interfaces of type “L” and NS interfaces of type “S” (see Figure 2) is F(NL , NS) = NLϵL + NS ϵS − kT ln(W )
(1)
where ϵL,S is the energy of an interface of type “L” and “S”, respectively, and W is the multiplicity corresponding to all possible sequences for a chain defined by the set of numbers (NS, NL). Because the entropic term is zero for both homogeneous structures in Figure 2B,C, the free energy is lowest for the larger particle made of wt protein and its formation is favored. When the N-terminus is removed, the range of accessible structures broadens. Figure 3 shows several examples organized by energy versus N, the total number of subunits. We observe the occurrence of circular chains of lower symmetry corresponding to heterogeneous sets of binding interfaces (here we show only one: N = NS + NL = 8). For the same number of subunits, open chains have higher energy than closed chains but may acquire lower free energy due to multiplicity (e.g., the (3,4) chains in Figure 3). We see how quickly the energy landscape can become quite complicated when multiple types of binding interactions are possible, which raises questions as to the mechanisms by which virus growth manages to navigate it so efficiently. Because of the astonishing speed with which certain viruses assemble, the process may bear some resemblance to the Levinthal paradox in protein folding. For instance, estimates of the assembly time of a 4.6 MDa CCMV particle consistent with bulk data set it at a few hundreds of milliseconds.25 This CCMV assembly is
Viruses are under evolutionary pressure to enclose their genomes in a protective shell without delay upon replication. In equilibrium experiments, such nanoparticle-templated viruscoat-assembly approaches could provide dissociation constants as a function of the radius of the template, thus providing valuable 3435
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ordered array. In LHCs, restricted dynamics and coherence in the orientations of transition dipoles in the complex are believed to prevent fluorescence quenching at equivalent concentrations of chlorophyll, which otherwise would lead to complete fluorescence suppression.29 Energy management in such photosynthetic systems relies on quantum coherence to funnel the photoexcitation energy toward a reaction center. Could LHCs inspire future VLPs that harness quantum coherence? What phenomena and properties could result from it? Such ideas have already started to be explored, with preliminary work on excited state dynamics in TMV-based systems confirming dependence on the locations at which chromophores are placed.30,31 A possible application to nanoscopic light sources of enhanced brightness that we are currently investigating in our laboratory is presented in Figure 4. Here, the idea is that instead of funneling
knowledge of the thermodynamic states corresponding to different protein tilings of the sphere and potentially on other shapes and tilings that are important in nanotechnology applications, as well. Moreover, for nanoparticles incommensurate with the lumen of canonical quasi-equivalent shells, it is possible that lower symmetry shells such as the (4,4) particle in the example of Figure 3 could be stabilized. Lower symmetry shells encapsulating nanoparticles could be interesting for the growth of non-close-packed lattices for optical metamaterials.28 A New Kind of Beacon. Templated strategies to virus construction exist in nature, too. Reoviruses have non-enveloped quasi-spherical particles built of two concentric, mutually stabilized protein shells. In this issue of ACS Nano, Brillault et al. show how simultaneous transient expression in plants of the main structural proteins, VP3 and VP7, of a reovirus, the Bluetongue virus (BTV), results in co-assembly of a doubleshell particle with the pseudo-T = 2 inner shell containing only VP3 and the T = 7 outer composed solely of VP7.1 The mechanisms by which these heteromultimeric protein complexes form are unknown, but sample homogeneity and yields are impressive, clearly pointing to strong scalability potential. Biomedical applications that could benefit from this research include the development of effective delivery vectors, safe and effective vaccines, and VLP production for the coexpression of enzymes for the manipulation of metabolic pathways in humans. Cargo loading tests to assess the potential of recombinant BTV as a VLP delivery vector were pursued in two ways: by expression of 120 copies of green fluorescent protein (GFP) and by selective bioconjugation reactions of fluorophores, both at the lumenal interface of the VP3 core. Fluorophore access to the interior was via diffusion through pores at the 5-fold axis of symmetry.
Figure 4. (A) Molecular model of the virus-like particle (VLP) based on a brome mosaic virus mutant having 180 chromophores (green) covalently bound to cysteines at the particle surface and an 11 nm diameter gold nanoparticle inside. (B) General schematic in frequency domain of an inhomogeneously broadened ensemble of N chromophores modeled as two-level systems and coupled to a single damped resonance corresponding to the surface plasmon (SP). Inhomogeneous broadening is expected to be reduced in VLPs with respect to other approaches toward generating coupled quantum-radiator complexes. Coupling to the SP resonance may further spectrally stabilize emission.
In this issue of ACS Nano, Brillault et al. show how simultaneous transient expression in plants of the main structural proteins, VP3 and VP7, of a reovirus, the Bluetongue virus (BTV), results in co-assembly of a double-shell particle with the pseudo-T = 2 inner shell containing only VP3 and the T = 7 outer composed solely of VP7.
the photoexcitation energy toward a reaction center like in photosynthetic systems, the multi-chromophore array relaxation may couple collectively into the surface plasmon mode of a metal nanoparticle (NP) core.32 It could also collectively couple into free space modes (i.e., into radiation).33,34 In coherent processes, the dependence of relaxation dynamics on the number of radiators is different than for ensembles of independent radiators. The focus of our current research in metal NP multi-chromophore VLPs interacting with light is to realize experimental conditions for coherent relaxation and unveil its mechanisms and possibilities for control of excited state decay pathways. Previous theoretical work and proof-of-principle experiments have suggested that losses in the localized surface plasmon resonance of metal NPs could be overcome by surrounding metal NPs with an optical gain medium in the form of a random dye-doped dielectric shell. This loss compensation scheme can be strong enough to lead to plasmon-assisted nanolasing.35,36 Could such bright, nanoscopic light sources be constructed via virus-enabled self-assembly? Could the fidelity of biological assembly provide for symmetry in the chemical environments of chromophores and, therefore, for reduced inhomogeneous broadening? Could symmetry, in turn, be manipulated via directed assembly, thus offering a way to control collective excited state dynamics? These questions open a
Interestingly, in GFP-loaded VLPs, the average distance between chromophores is ∼6.5 nm. This distance is equivalent to ∼50 mM concentration in solution. At this concentration, fluorescence from synthetic dyes would be completely suppressed. Green fluorescent proteins are less prone to selfquenching than synthetic dyes but are still expected to exhibit significant dimming of fluorescence at high concentrations. Interestingly, fluorescence from GFP−BTV constructs in the Brillault et al. paper appears to be easily detectable. The possibility of fluorescence quenching suppression, as well as the scale and structural organization of the VLPs, call to mind certain light-harvesting complexes (LHC) encountered in photosynthetic systems, in particular, the LHCs of chlorosomes in green sulfur bacteria. Similar to these multi-chromophore systems, VLPs are composed of a multi-chromophore, isometrically 3436
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new window of research with engineered VLPs and, together with the scalability and ever-increasing complexity attainable by synthetic biology approaches of the kind illustrated by Brillault et al., offer yet another reason to believe in an exciting outlook for the physical virology field.
AUTHOR INFORMATION Corresponding Author
*E-mail:
[email protected]. ORCID
Bogdan Dragnea: 0000-0003-0611-2006 Notes
The author declares no competing financial interest.
ACKNOWLEDGMENTS The author thanks the CBET program at the National Science Foundation, the Basic Energy Sciences division of the U.S. Department of Energy (Award DE-SC0010507), the U.S. Army Research Office (Award W911NF-13-1-0490), and the Human Frontier Science Program (Award RGP0017/2012) for funding work in areas pertaining to this Perspective. REFERENCES (1) Brillault, L.; Jutras, P. V.; Dashti, N.; Thuenemann, E. C.; Morgan, G.; Lomonossoff, G. P.; Landsberg, M. J.; Sainsbury, F. Engineering Recombinant Virus-Like Nanoparticles from Plants for Cellular Delivery. ACS Nano 2017, DOI: 10.1021/acsnano.6b07747. (2) Wilkinson, L. The Development of the Virus Concept as Reflected in Corpora of Studies on Individual Pathogens. Lessons of the Plant Viruses−Tobacco Mosaic Virus. Med. Hist. 1976, 20, 111− 34. (3) Vinson, C. G.; Petre, A. W. Mosaic Disease of Tobacco. Bot. Gaz. 1929, 87, 14−38. (4) Bernal, J. D.; Fankuchen, I. X-Ray and Crystallographic Studies of Plant Virus Preparations: I. Introduction and Preparation of Specimens. II. Modes of Aggregation of the Virus Particles. J. Gen. Physiol. 1941, 25, 111−146. (5) Culver, J. N.; Brown, A. D.; Zang, F.; Gnerlich, M.; Gerasopoulos, K.; Ghodssi, R. Plant Virus Directed Fabrication of Nanoscale Materials and Devices. Virology 2015, 479−480, 200−212. (6) Moradi, M.; Li, Z.; Qi, J.; Xing, W.; Xiang, K.; Chiang, Y.-M.; Belcher, A. M. Improving the Capacity of Sodium Ion Battery Using a Virus-Templated Nanostructured Composite Cathode. Nano Lett. 2015, 15, 2917−2921. (7) Rahman, M. M.; Ö lçeroğlu, E.; McCarthy, M. Scalable Nanomanufacturing of Virus-Templated Coatings for Enhanced Boiling. Adv. Mater. Interfaces 2014, 1, 1300107. (8) Murphy, J. F. Applied Aspects of Induced Resistance to Plant Virus Infection. In Natural Resistance Mechanisms of Plants to Viruses; Loebenstein, G., Carr, J. P., Eds.; Springer, 2006; pp 1−11. (9) Fraenkel-Conrat, H.; Williams, R. C. Reconstitution of Active Tobacco Mosaic Virus from its Inactive Protein and Nucleic Acid Components. Proc. Natl. Acad. Sci. U. S. A. 1955, 41, 690−698. (10) Bancroft, J. B.; Hiebert, E. Formation of an Infectious Nucleoprotein from Protein and Nucleic Acid Isolated from a Small Spherical Virus. Virology 1967, 32, 354−356. (11) Caspar, D. Self-Control of Self-Assembly. Curr. Biol. 1991, 1, 30−32. (12) Caspar, D. L. D.; Klug, A. Physical Principles in Construction of Regular Viruses. Cold Spring Harbor Symp. Quant. Biol. 1962, 27, 1− 24. (13) Chariou, P. L.; Lee, K. L.; Pokorski, J. K.; Saidel, G. M.; Steinmetz, N. F. Diffusion and Uptake of Tobacco Mosaic Virus as Therapeutic Carrier in Tumor Tissue: Effect of Nanoparticle Aspect Ratio. J. Phys. Chem. B 2016, 120, 6120−6129. 3437
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