Structure and assembly of viruses

For the majority of viruses, including major human pathogens, these containers exhibit high degrees of structural organisation and symmetry. Many open questions in virology can therefore be addressed through the lens of viral geometry. The team have demonstrated that group, graph, tiling and lattice theory, in partnership with biophysical modelling, bioinformatics, and stochastic simulations, can act as drivers of discovery in virology.

Studying symmetries of viruses and their implications for virus architecture, Professor Twarock and her team discovered mathematical and physical principles underpinning virus assembly and viral evolution. For example, they developed novel approaches to decipher the cryptic self-assembly instruction manual for the production of infectious virus particles. They also developed models to study how the cooperative action of multiple dispersed RNA-protein contacts enables viruses to overcome a viral equivalent to Levinthal’s paradox, ensuring efficient capsid formation along only a small subset of the combinatorially possible assembly pathways. This research played a key role in the discovery of packaging signal-mediated assembly in collaboration with the Stockley lab at the University of Leeds.

In the recent project ‘New perspectives for antiviral therapy: the regulatory roles of genomic RNA in virus assembly, infection and evolution’ the interdisciplinary York/Leeds team provided new insights into the molecular mechanisms behind virus assembly. They identified the molecular details of the RNA-protein contacts underpinning the packaging signal-mediated assembly in a wide range of viral families, including Picornaviruses and recently also coronaviruses. This work laid the foundation for a new type of antiviral strategy, and the Universities of York and Leeds jointly hold patents for the exploitation of these discoveries.

In the project ‘Geometry as a key to the virosphere: Unmasking the fundamental roles of geometry in virus structure, evolution and pathology’ funded by her Engineering and Physical Sciences Research Council (EPSRC) Established Career Fellowship and her Royal Society Wolfson Fellowship, Professor Twarock moreover addresses the role of symmetry breaking in viral life cycles, explaining anomalies in the structures of larger and more complex viral geometries. Recent work with US collaborators under the auspices of this programme also resulted in the discovery of a fundamental mathematical principle orchestrating virus architecture, that encompasses the seminal Caspar-Klug theory as a special case and covers in addition hitherto unexplained structures. Amongst others, this work shed new light on geometric constraints on viral evolution and revealed geometric ways in which larger viral geometries could evolve from smaller ones via specific (gyrated) lattice intermediates. Such a predicted pathway has recently been observed in direct evolution experiments at the ETH Zurich.

Moreover, Professor Twarock and US collaborators recently established a link between capsid geometry and disassembly, that offers a possible explanation for the unequal frequency of distinct viral geometries in nature,Professor with implications for protein container design in virus nanotechnology.