The M2 channel with the proton-conducting water wire disrupted by the presence of the anti-flu drug amantadine. The lipid bi-layer membrane is not shown so that the channel can be seen more clearly. Image courtesy of Hanning Chen

The symptoms appear suddenly and often—a continuous fever, shaking chills, body aches, muscle pain, fatigue, loss of appetite and nausea.

In most cases, home treatment of the viral illness influenza is all that is needed for recovery, but sometimes “the flu” can lead to life-threatening complications.

University of Utah chemistry professor Gregory Voth and his team are using the TeraGrid to further drug design and virology, studying the influenza A M2 channel and its effect on proton transport and viral replication.

Gateway to viral replication

The M2 channel is believed to play a key role in the viral life cycle, acting as a conduit for transport of the protons that facilitate viral replication. The M2 channel also exhibits unique pH-gated behavior, as opposed to the voltage-gated behavior of many other proton channels.

According to Voth, the challenge of understanding proton transport requires computational simulations benchmarked against experimental results.

“I’m a huge fan of the TeraGrid,” says Voth, who is one of the largest TeraGrid users. “The TeraGrid cluster systems are phenomenally useful. There isn’t any doubt that these resources have enabled our research.”

The calculation of proton transport pathways requires a novel computational methodology combined with extensive simulation over many fast processors to achieve meaningful statistical convergence.

The M2 channel research team have solved part of the proton transport mystery, explaining how the anti-flu drug amantadine blocks the M2 channel to shut down the transport of protons essential to viral replication. Image courtesy of the Center for Biophysical Modeling and Simulation, University of Utah

Pushing to the frontiers

Despite these challenges, Voth believes that the computer simulations made possible by the TeraGrid play a critical role in determining the mechanism of proton transport.

“One of the hallmarks of our research is that we avoid cutting corners on accurate modeling to the extent possible,” Voth says.

“We set very high standards and constantly refine and validate the model. We also keep pushing the frontiers of what we’re doing in terms of its complexity and challenge.”

Using the TeraGrid, Voth and his research group have solved part of the proton transport mystery: Their study explains how the M2 channel operates as a proton conductor in responding to the acidic conditions on either side of the cell membrane.

The study also explains how the anti-flu drug amantadine blocks the channel and causes it to shut down.

Voth’s next step is to study the strains of M2 that do not bind amantadine, to see if other compounds might be effective anti-flu drugs.

- Faith Singer-Villalobos, Texas Advanced Computing Center