Atomistic detail

Potassium channel model lights the way for simulations of molecular machines

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	A visualization of the modeled three-dimensional structure of the potassium-channel protein, performed on the ORNL Jaguar supercomputer.

Scientists are using resources at the National Center for Computational Sciences to simulate in unprecedented detail the voltage-gated potassium channel, a membrane protein that responds to spikes of electricity by changing shape to allow potassium ions to enter a cell.

"The study will serve as a future road map for simulating, visualizing and elucidating the workings of molecular nanomachines," says professor Benoît Roux of Argonne National Laboratory and the University of Chicago.

In essence, a voltage-activated ion channel is a nanoscale device acting as an electric switch, he says. With University of Illinois at Urbana-Champaign researchers Klaus Schulten and Emad Tajkhorshid, Roux uses the Leadership Computing Facility at ORNL to model the channel in its open and closed states and determine the gating charge driving the change in conformation between the two states.

If the switch operates normally, the potassium channel opens when activated and closes when resting. But if gating malfunctions-and it can go awry in various ways-cardiovascular or neurological disease can result. The important functions of potassium channels in excitable cells make them good drug targets.

Roux's team is using a computer program called Rosetta to predict the three-dimensional structure of the potassium-channel protein. For a given sequence of amino acids, Rosetta conducts a large-scale search for three-dimensional protein conformations that are especially low in free energy and assumes the native state is the one with the least free energy. The group found that simulations of the open and closed states are stable. Assessing stability is critical to supporting the model's validity.

In a step toward achieving their long-term goal of understanding how membrane-associated molecular protein machines function, the researchers simulated the motion of all atoms in the system using a molecular dynamics code for parallel processing that was developed in Schulten's lab.

The code, called NAMD, uses Newton's laws and an energy function to simulate protein behavior in steps on the order of one femtosecond, or trillionth of a second. By looking at how the potassium channel moves in tiny, ultrafast increments, researchers can build a biologically meaningful picture of its dynamics.

Roux's group received funding from the National Institutes of Health and an allocation of NCCS supercomputer time through a DOE program called INCITE (for Innovative and Novel Computational Impact on Theory and Experiment). In 2007 the researchers used about 2.5 million processor hours on the NCCS's Cray XT Jaguar supercomputer to model the behavior of systems with up to 350,000 atoms. "We are in the process of unraveling the atomistic basis for the coupling between a voltage-gated channel and the transmembrane electric potential," says Roux, whose group has received a 2008 INCITE grant of 3.5 million hours on Jaguar to continue the studies.