Penn biophysicists create new model for protein-cholesterol interactions in brain and mus...(be essential for activation of the recep...)

"The result was surprising because, according to most traditional biological models, cholesterol is part of the membrane, not part of the protein," Grace Brannigan, a researcher with the Center for Molecular Modeling at Penn, said. "Our model takes cholesterol out of a background role in the protein's structure and function and puts it on center stage."

Researchers used prior data on how the receptor depends on cholesterol to function plus a computer cluster to run simulations of some 230,000 atoms and their interactions over time. From the raw data, researchers used visualization software to create a model of behavior between the protein and the cholesterol required to function properly.

The study focused on the nicotinic acetylcholine receptor, an ion channel found in both brain and muscle cells. The neurotransmitter acetylcholine, released by upstream nerve cells, binds to portions of the protein on the outside of brain and muscle cells causing the channel to open and allow ions to cross the membrane. Anesthetics, for example, close the channel, which can reduce sensations and cause the memory loss associated with being "put under."

The receptor is a cation-selective channel central to both neuronal and muscular processes and is considered the prototype for ligand-gated ion channels, leading to decades of study to determine its structure. Penn researchers sought to further understand the structure recently determined through cryo-electron microscopy by British and Japanese researchers. Measuring structural details is a difficult task for any protein embedded within a membrane, which can be easily destroyed during the extraction process. The published structure included large, mysterious holes in the protein density.

"It's like looking at the shape of a lock and realizing that you've had the key in your pocket the whole time," Jerome Henin, a researcher with the Center for M
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