‘Virtual virus’ unfolds the flu on a CPU

Their research is 'nothing to sneeze at,' the researchers suggest
February 10, 2015

Future simulation work will involve the influenza A virus in close apposition with a host cell membrane (credit: H. Koldsø/Oxford)

By combining experimental data from X-ray crystallography, NMR spectroscopy, cryoelectron microscopy and lipidomics (the study of cellular lipid networks), researchers at the University of Oxford have built a complete model of the outer envelope of an influenza A virion for the first time.

The simulation may help scientists better understand how the virus survives in the wild or find new ways to combat it.

The approach, known as a coarse-grained molecular dynamics simulation, has allowed them to generate trajectories at different temperatures and lipid compositions, revealing various characteristics about the membrane components.

How to simulate a virus

Their computer simulation begins by rendering the virus as a relatively large, 73-nanometer ball of loosely packed lipids. This ball then relaxes down into a smaller, 59-nanometer virion within 300 nanoseconds. The viral spike proteins are then embedded into the lipid envelope individually, before adding solvent to the system.

“In the current publication, this is just a single virion in a water droplet — but what could really get interesting is if we start putting in other molecules of interest, such as therapeutic agents,” said Tyler Reddy, a postdoctoral fellow at the University of Oxford.

Here’s what they learned from the simulation:

  • The viral spike proteins protruding from the virion’s membrane spread out, rather than aggregating close together. This is key to the strength of the interactions between influenza A virions and host cells, which are determined by the number of spike proteins that can engage with receptors. “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 said.
  • Forssman glycolipid had a role in preventing protein aggregation and slowing down protein diffusion, so it would be important to include glycolipids in future virion simulations given their influence on the biophysical properties observed. The extended sugar head groups of glycolipids may mask antibody accessibility of the M2 proton channels in the flu envelope — the target of commonly prescribed anti-influenza drugs based on adamantane derivatives.

Understanding the membrane envelope’s structural dynamics also provides insight into the wide-ranging survival times of the virion in different environments, such as fresh-water rivers. Previous studies have indicated that the presence of influenza A in rivers has allowed waterfowl to be simultaneously exposed to source flu strains and residual anti-viral compounds excreted by local human populations, potentially giving rise to drug-resistant influenza strains. Reddy’s simulation currently monitors the virion’s stability on the microsecond scale, and it will be a challenge to assess stability over much longer time scales.

“We are a long way from being able to perform molecular dynamics simulations that span the year time scale,” Reddy said. “Nonetheless, we now have a platform for looking at influenza A virion behavior in silico (in a computer simulation)  and perhaps certain compounds or solutions could be used to accelerate destabilization on an observable time scale.

“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 criticize and help improve the model.”

Hopefully, this information will go viral. …

Abstract for Nothing to sneeze at: a dynamic and integrative computational model of an influenza A virion

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. This represents the first set of microsecond-scale molecular dynamics simulations of an enveloped virion in explicit solvent that we are aware of. We report results for a set of simulations at different temperatures and with varying lipid compositions. The Forssman glycolipid, which is prevalent in the influenza A lipidome, influences several biophysical characteristics of the virion model, including diffusion and clustering of proteins and lipids. The distribution of peplomers on the virion surface is consistent with accessibility to bivalent antibodies. The distances of binding sites for host cell sialic acid-containing receptors have been analyzed in the virion model for a variety of planar host cell membrane attack orientations. The relatively rigid membrane of the influenza A virion model exhibits a number of biophysical properties consistent with experimental measurements, and may serve as a useful platform for in silico assessment of virion behaviour.