From proteins to virus particles: the structure and function of virions

Structural biology aims to understand how the shapes of the molecules of life, such as viral proteins, direct their functions. This is achieved by experimental determination of the 3D shape of biological molecules at the level of their individual atoms. Atomic structures can be combined with mathematical models of how molecules might move (molecular dynamics) and how they might evolve to evade host defences. Understanding the structure, dynamics and evolution of viral proteins can give researchers new ways to think about viral infections which can be tested in the laboratory. In this programme we will bring together expertise in structural biology (Bhella, Carter), molecular dynamics (Grove), mathematical modelling (Illingworth) and molecular and compositional biology (Hutchinson) to study the structure and function of virus particles (virions) of influenza viruses, coronaviruses and respiratory syncytial virus.

The molecular mechanics of viral proteins are a fundamental determinant of viral infection, transmission, and disease. Viral evolution modulates protein structure and mechanics in response to diverse selection pressures (e.g., adaptation to a new host or evasion of immunity); but evolution is also constrained by a requirement to preserve essential protein function. This programme brings together advanced methods in structural and molecular biology, microscopy, evolutionary biology, and mathematical modelling to investigate how virions assemble, transmit viral genomes and how evolution shapes their functions. We will conduct three collaborative work packages that investigate the virions of three notable respiratory pathogens: influenza A virus (IAV), severe acute respiratory syndrome virus type 2 (SARS-CoV-2) and respiratory syncytial virus (RSV).

WP1 We will develop an integrated mechanistic understanding of membrane fusion by SARS-CoV-2 spike and IAV haemagglutinin (HA). We will investigate how spike function has evolved in variants of concern; how proteolytic activation of spike is coordinated during virus assembly/entry; how protein disorder in spike regulates virus entry; and, using this knowledge, consider new spike-targeted interventions. To inform the development of models of fusion protein evolution over long timescale, we will generate a comprehensive dataset of HA structures spanning IAV’s history of transmission in humans over decades.

WP2 We will identify the molecular determinants of filamentous virion formation. We will investigate how respiratory syncytial virus (RSV) and IAV assemble helically ordered, enveloped particles at the host-cell plasma membrane. We will assess how flexible, filamentous architectures support their function, and how incorporation of viral and host gene products is coordinated.

WP3 We will build an understanding of how heterogeneity in viral populations drives their interactions with hosts. We will ask how interactions between heterogeneous populations of viral particles determine the transmission and evolution of IAV.

Our work will deliver fundamental knowledge and build a framework for the next generation of molecular virology, shaped by close integration of scientists and expertise from a broad range of disciplines. Notably, the knowledge, concepts and techniques developed here are broadly translatable to other viruses being investigated at the CVR and beyond.