Flu shot: NMR spectroscopy helps with model building

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  • Published: Feb 15, 2015
  • Author: David Bradley
  • Channels: NMR Knowledge Base
thumbnail image: Flu shot: NMR spectroscopy helps with model building

Combination computation

Tackling the ongoing challenge of influenza infectivity would benefit greatly from a molecular understanding of why the influenza A virion exhibits seasonal patterns of infectivity and has wide-ranging survival times in different environments. A computational approach to the study of the behaviour of the virion that focuses on the poorly-understood structural and dynamic role of the lipids is presented here. We have combined experimental data from X-ray crystallography, NMR spectroscopy, cryoelectron microscopy, and lipidomics to build a full-scale computational model of the influenza A virion.

The combination of experimental data from nuclear magnetic resonance spectroscopy, X-ray crystallography, cryoelectron microscopy and lipidomics has allowed researchers to build the first complete model of the outer envelope of an influenza A virion.

Seasonal influenza is an acute and highly contagious viral infection that can kill. The World Health Organisation (WHO) estimates that between 3 and 5 million people are infected annually during seasonal epidemics and that between a quarter and half a million die from the disease, commonly those with other chronic illnesses or among other at-risk groups, such as the elderly, infants, pregnant women and people with compromised immune systems. Tackling this perennial challenge could be made a lot easier if we had a clearer view of the molecular character of the influenza A virion.

Researchers have now used insights obtained by others around the world through NMR spectroscopy and other techniques to help them build a computational model of the behaviour of the virion that focuses on the little-understood structural and dynamic roles played by lipids. The team also utilised X-ray crystallographic data, cryoelectron micrographs and lipid profiling to make the picture clearer still.

Virion

The University of Oxford team now has a complete model of the outer envelope of the viral particle, which was studied over the course of several coarse-grained molecular dynamics simulations. The model has allowed them to generate trajectories at different temperatures and lipid compositions, which they report shows several characteristics of the membrane components--any one of which might improve our understanding of viral survival and perhaps reveal new targets at which medicinal chemists might aim novel antiviral drugs.

Their simulation is initiated with a structure formed as a 73-nanometre ball of loosely packed lipids and is relaxed down to a 59-nanometre virion in a fraction of a second, 300 nanoseconds, to be precise. The viral spike proteins are then embedded into this model of the lipid envelope one by one and then solvent molecules - water - injected into the simulation to allow movement and restructuring that might occur in the physiological "wild". The next, perhaps more interesting part of the project will be to add data for antiviral agents to this virion in a water droplet model to see how those drugs might affect its stability. Tyler Reddy, a postdoctoral fellow at Oxford described the research at the 59th annual meeting of the Biophysical Society in Baltimore, Maryland, USA in February.

Reddy and colleagues have demonstrated that those embedded spike proteins do not aggregate--instead they are spread out across the virion's membrane surface. This, the team says, is critical to the strength of any interactions between influenza A virions and host cells that it attempts to invade and hijack for its own replication.

Spiked

"If the separation of the spike proteins is compatible with the 'arms' of Y-shaped, bivalent antibodies, this information might be exploited in therapeutic design, so that two antigens may be bound simultaneously for enhanced association," Reddy explains. Reddy's work builds on that of Daniel Parton who is a researcher at the Memorial Sloan Kettering Cancer Center in New York City and co- author on the paper.

A better understanding of membrane stability could provide clues as to how the virus can survive and spread from fresh water rivers and so be a risk factor for infection of waterfowl and putative transfer to people who come into contact with them. Reddy's simulation currently monitors the virion's stability on the microsecond scale, and it will be a challenge to assess stability over the sort of timescales that would see it transported in river water and to infect waterfowl.

"We are a long way from being able to perform molecular dynamics simulations that span a year," Reddy said. "Nevertheless, we now have a platform for looking at influenza A virion behaviour in silico, and perhaps certain compounds or solutions could be used to accelerate destabilization on an observable timescale," Reddy adds. "We're making the coordinate data freely available in the hopes that other groups have interesting ideas for use with this model as well, and so that they can critique and help improve the model."

"The computational model of the influenza A virion does not account for the internal genetic material nor the M1 matrix protein that lines the inner leaflet of the lipid envelope," Reddy told SpectroscopyNOW. "So these are details we'd like to incorporate in the future." He adds that, "Perhaps more important is the addition of glycans to the spike proteins on the surface of the virion, because these could be important in the interaction between the flu virus and antibodies or therapeutics. We're currently focusing on how the virion model interacts with a host cell membrane - this is an even bigger simulation. In a sense we've done the necessary 'boring bit' of making sure the influenza A virion model is sensible and does not fall apart in silico, and we are now in a position to start testing the interaction of the virion with membranes and small molecules."

Reddy also adds that he has been working on models of other enveloped virions and suggests that ideally some of these will provide a platform for in silico screening too. "The dream is to keep producing high-quality virion models that other researchers can use - we definitely think that it is important to make the coordinates freely available for criticism and  mprovement. Maybe some day full-scale virion models will be used in drug/vaccine development pipelines, since they account for avidity and polyvalence in ways that smaller models cannot. However, we must be cautious with these predictions - a lot of improvements have to be made to the models and the computational power to perform therapeutically relevant simulations is likely to be large."

Related Links

Structure, 2015, in press: "Nothing to sneeze at: a full-scale computational model of the human influenza virion"

Article by David Bradley

The views represented in this article are solely those of the author and do not necessarily represent those of John Wiley and Sons, Ltd.

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