Abstract
Virus-like particles (VLPs) have significant potential as artificial vaccines and drug delivery systems. The ability to control their size has wide ranging utility but achieving such controlled polymorphism using a single protein subunit is challenging as it requires altering VLP geometry. Here we achieve size control of MS2 bacteriophage VLPs via insertion of amino acid sequences in an external loop to shift morphology to significantly larger forms. The resulting VLP size and geometry is controlled by altering the length and type of the insert. Cryo electron microscopy structures of the new VLPs, in combination with a kinetic model of their assembly, show that the abundance of wild type (T = 3), T = 4, D3 and D5 symmetrical VLPs can be biased in this way. We propose a mechanism whereby the insert leads to a change in the dynamic behavior of the capsid protein dimer, affecting the interconversion between the symmetric and asymmetric conformers and thus determining VLP size and morphology.
Highlights
Virus-like particles (VLPs) have significant potential as artificial vaccines and drug delivery systems
We have discovered that insertion of particular amino acid sequences at a certain position in the coat protein (CP) protein, results in a significant shift towards larger VLP sizes
In order to understand how the insertion of additional amino acid sequences in an external loop triggers this effect, we developed a kinetic model of particle assembly
Summary
Virus-like particles (VLPs) have significant potential as artificial vaccines and drug delivery systems. 1234567890():,; Protein cages, convex polyhedral protein containers selfassembled from multiple copies of identical protein subunits, are pillars of nanotechnology They include naturally occurring virus capsids (virus-like particles, VLPs) as well as a plethora of particles with diverse symmetries. Given their structures, protein cages are obvious candidates for development as vaccines (through addition of relevant antigens on their exterior surfaces) and as drug delivery systems (through encapsulation of relevant therapeutic molecules in their hollow cores)[1,2,3]. A protein cage of bacterial origin, has shown a wide range of different forms, including cages of different sizes and even a protein tube depending on buffer conditions[10] In all of these cases, the spectrum of variant morphologies, and how assembly can be biased to achieve desired structural outcomes, are unknown. According to Euler’s theorem, exactly 12 five-fold clusters are needed to build a closed shell, and for the protein capsids we observe, both types of dimers are required to form a closed protein capsid
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