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Posted: Dec 20, 2007

Artificial virus shells as practical nano containers

(Nanowerk Spotlight) In 1954, Richard Buckminster Fuller was granted U.S. Pat. No. 2,682,235 for geodesic domes, a method of enclosing space in architectural applications. The geodesic dome combines the structural advantages of the sphere (which encloses the most space within the least surface, and is strongest against internal pressure) with those of the tetrahedron (which encloses least space with most surface and has the greatest stiffness against external pressure). Subsequently, soccer ball shaped carbon molecules known as fullerenes or buckyballs were named for their resemblance to a geodesic sphere. But is not only certain carbon molecules where Nature uses sphere-like forms. Spheres can be found at all scales in both the inanimate and living world for the basic physical property of encapsulation. Spherical virus capsids (a capsid is the protein shell of a virus), for example, enclose space by using the geometry of the icosahedron, thus exploiting the economy of this form in terms of both surface area-to-volume ratio and genetic efficiency of subunit-based symmetric assembly. Many viruses' capsids use icosahedral symmetry to form particles ranging from 20 to 200 nanometers in size. Researchers have now begun to copy Nature's icosahedral-symmetry design principles for molecular containers, which could solve the problem of designing and synthesizing stable molecular containers having very large interior.
"The idea of forming nonprotein molecular containers by total synthesis and assembly of small molecules has a rich history and is an active area of research" Dr. Ehud Keinan explains to Nanowerk. "The field of molecular recognition is rapidly moving not only toward biomedical applications but also toward nanotechnology. Significant progress has been made in the design and synthesis of fully enclosing molecular assemblies that have inner dimensions of up to 15 Â (1 Angstrom - 0.1 nanometer) and volumes of up to 1,500 cubic Angstroms and are capable of encapsulating molecules that range in size from water to steroids. However, to the best of our knowledge, no synthetic strategy that incorporates the icosahedral symmetry of viral capsids has been reported."
Self-assembling virus model
Four snapshots from molecular dynamics simulations. (A) Trimer (at 600 ps). (B) Tetramer (at 1.7 ns). (C) Pentamer (at 4.1 ns). (D) Half-sphere hexamer (at 4.9 ns). (Reprinted with permission from PNAS)
Keinan is the Benno Gitter and Ilana Ben Ami Professor of Chemistry at the Israel Institute of Technology (Technion) in Haifa. He also teaches at the Scripps Research Institute in La Jolla, CA. Together with his team he developed a design that is based on self-assembly of synthetic pentagonal tiles to produce containers that have exterior diameters of 2550 Â and interior volumes in the range of 15,000 1,000,000 cubic Â. The findings have been reported in the December 18, 2007 online edition of Proceedings of the National Academy of Sciences ("Chemical mimicry of viral capsid self-assembly" – open access article).
When a virus with icosahedral structure starts to replicate itself, it uses the mechanisms of the infected host cell to synthesize pentagon-shaped subunits that then self-assemble into the full capsid.
"In Nature, there is only really one economical way to make balls," says Keinan. "Nature takes repeated tiles with icosahedral symmetry - using pentagons just like a soccer ball. We designed pentagonal tiles that can bind to one another, self-assembling to form a hollow sphere."
Previous in vitro experiments with viral capsids provided proof of the feasibility of self-assembling containers that have icosahedral symmetry with 60 identical structural units ("The familiar and the unexpected in structures of icosahedral viruses").
"We decided to initially explore the generality of the phenomenon by producing autofabricated physical models of viral assembly units, choosing to model the pentameric assembly intermediate of the poliovirus" says Keinan. "These structures are composed of five copies each of four individual protein chains, and they make a well shaped five-sided assembly with complementary shapes and electrostatic charges along the five edges. By appropriate placement of oriented magnets as analogs to the electrostatic complementarity, we produced a model that mimics the self-assembly of the virus from twelve pentameric assembly intermediates."
It is fascinating to watch a movie where 12 pentagonal plastic tiles containing small magnets, placed in a container and shaken with the appropriate strength, result in a stable closed shell, usually within 12 min.
Self-assembling virus model
Movie: Self-assembling virus model
Keinan explains that the key aspects of this model were the fivefold symmetric tiles, the appropriate curvature at the tile interfaces, and the geometric and magnetic complementarity of the interfaces. "Although intellectually we knew that this type of self-organization occurs spontaneously, watching it happen from random shaking on the macroscopic scale was inspirational" he says.
One question that arises from this physical experiment of course is why this assembly take place so rapidly? "Clearly the answer is in the symmetries of the tiles and capsid and the redundancy of the interfaces; they are all self-complementary and there are five equivalent faces per tile, and there is only one most stable configuration, the assembled capsid" says Keinan. After all, there are 9.75 quadrillion (a number with 15 zeroes) ways for 12 pentagonal tiles to be put together.
Having demonstrated their tile self-assembly on a macroscopic scale with plastic tiles, Keinan and his team then translated these models to the molecular scale by using the pentagonal core of the hydrocarbon corannulene (C20H10), also nicknamed 'buckybowl', because of its fivefold symmetry, appropriate curvature, and rigidity.
"Our computational models based upon optimized quantum mechanical geometries and molecular dynamics simulations indicate that appropriately designed corannulene derivatives can self-assemble" says Keinan.
So far, the team have generated a half-sphere in the lab, but they are confident that further work will lead to an intact structure. At around 3nm wide, these spherical containers are on a scale between fullerenes and viral capsids.
Keinan's methodology could solve the problem of designing and synthesizing stable molecular containers having very large interior. This has never been achieved with non-protein subunits. He points out that such structures can serve numerous functional roles, including a) a new platform for alternative, safe immunization, b) synthesis of nanoparticles with uniform size, and c) a new approach to drug delivery and, with larger chemical capsids, even gene delivery.
By , Copyright Nanowerk LLC

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