HPCwire: Supercomputer Models Simulate Molecular Machinery

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April 11, 2008

Supercomputer Models Simulate Molecular Machinery

by Dawn Levy

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April 4 -- We're not robots, but the human body has machine-like aspects. That's especially true at the scale of billionths of a meter, the size of atoms and small molecules. A great example of a molecular machine is a membrane protein that responds to spikes of electricity by changing shape to allow potassium ions to enter a cell. Scientists are now using resources at the National Center for Computational Sciences (NCCS) to simulate the voltage-gated potassium channel in unprecedented detail.

"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 Oak Ridge National Laboratory 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. Muscle, heart, nerve, and secretory cells produce and respond to electrical signals, earning them the name "excitable cells." The important functions of potassium channels in excitable cells make them good drug targets. Other voltage-gated channels allow selective entry of sodium and calcium ions and are also promising targets.

The potassium channel is made of four identical protein subunits. Each contains segments of amino acids that cross the cell membrane six times like a switchback mountain trail. Two transmembrane segments from each subunit come together to form a pore through which only potassium ions may enter or leave.

The voltage sensor is the other important functional part of the potassium channel. Formed by four transmembrane segments surrounding the pore, the sensor responds to changes in electric potential. In a process called gating, the protein switches its shape to allow or block passage of ions across the cell membrane in response to a change in voltage.

Voltage-gated ion channels allow different ions and charges to gather on each side of a cell's membrane. In a nerve cell, potassium is abundant inside, and sodium, an ion that works with potassium to propagate nerve impulses, is plentiful outside. At rest the cell's membrane potential -- maintained by a predominant potassium ion conductance -- is slightly negative (polarized). When a hormone, drug, or neurotransmitter binds to a receptor on the neuron, stimulating it, a chain reaction begins that discharges the membrane potential as a tiny electrical current. When the cell becomes excited, it depolarizes, and sodium channels open. Because ions and charges flow from areas of high to low concentration, sodium flows in, further depolarizing the local membrane. Nearby potassium channels respond by opening their gates, allowing potassium to flow down its electrochemical gradient to restore the resting membrane potential. The result? Channels open, inactivate, and close in sequence. The membrane potential changes quickly and transiently, propagating the signal down the nerve like a line of falling dominos.

Gating is the key

What makes the nerve impulse possible in the first place is cellular choosiness for specific ions, or voltage-activated gating. To understand its mechanism, the researchers first aim to determine the channel's structure in its open and closed states. X-ray crystallography, the best method since the late 1950s for determining the structures of proteins, is employed to analyze potassium channels obtained from rat brain tissue. Today, it provides an incomplete picture of the atomic-level structure of the open channel, and no x-ray structure exists for the closed channel. Preparing membrane proteins for x-ray diffraction studies is very difficult because the proteins have to be crystallized under conditions different from their home environment, the cell membrane.

Roux's team is using a computer program called Rosetta to predict the three-dimensional structure of the potassium-channel protein. The group found that simulations of the open and closed states are stable. Assessing stability is critical to supporting the model's validity. Collaborator Vladimir Yarov-Yarovoy, a research assistant professor at the University of Washington, recently adapted Rosetta to better predict the behavior of proteins embedded in membranes.

"Rosetta predicts protein structure starting with amino acid sequence information alone, without any starting template structure," Yarov-Yarovoy says. Strings of amino acids (primary structure) link through hydrogen bonds to form pleats and helices (secondary structure) that fold to form three-dimensional proteins (tertiary structure) that can associate with other proteins (quaternary structure). 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.

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