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Fat Enough for Two Belts

Christopher Brodie

It sounds like a joke by the late comedian Rodney Dangerfield. "My uncle is so fat, he needs two belts." But high-density lipoprotein or HDL, the so-called "good" cholesterol, actually does consist of two protein belts cinched around a tiny disk of fat, according to a study published in the March 2007 issue of the Journal of Structural Biology. Computer simulations described in the paper predict  that this structure forms spontaneously within microseconds from a chaotic mix of protein and lipid molecules.

HDL acts like a molecular sheepdog in the body, rounding up cholesterol from the blood and herding it to the liver for breakdown. Despite its importance, fundamental questions about HDL, such as, "how does it form?" and "what does it look like?" remain.

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The HDL particle begins as a pair of apolipoprotein A-I (apo A-I) proteins, which collect lipids into a disk and, eventually, a sphere. Thus, the size and shape of HDL varies with the number of lipids it contains, making direct observation difficult. "This is one of those opportunities where only the computer can show how the protein does its job," says senior author Klaus Schulten of the Beckman Institute, part of the University of Illinois at Urbana-Champaign. But for a complex of this size, atom-by-atom simulations are limited to a few nanoseconds—too short to see the process of aggregation. Instead, Schulten's team used a "coarse grained" computer model, which grouped atoms together to ease the computational burden.

Snapshots from the simulation (above, right) show ropy apo A-I proteins (blue and orange) and a spray of lipids (gray). From an initially disordered state (a), the molecules quickly form clumps to hide their hydrophobic parts from the surrounding water (b). Within a microsecond, the pieces unite to form a single lipid-protein aggregate (c); the final structure (e) emerges after a period of additional wriggling (d). Data from a paper now in preparation suggest that this terminal, double-belted structure takes about 10 microseconds to form.

In supporting the double-belted model of HDL, the simulation disproved Schulten's own hypothesis, the "picket fence" model. Even simulations that started with apo A-I making zigzag pickets around the disk soon reverted to a double-belted shape.

The paper prompts two important follow-up questions. First, how sensitive is the model to the starting concentration of lipids? Second, given that these HDL particles are so difficult to observe in real life, how can the model be tested?

In recent months, graduate student and first author Amy Shih has answered both questions in papers awaiting publication. In a series of new simulations, Shih describes changes in the HDL structure with varying concentrations of lipids. She is also collaborating with Stephen Sligar, another Beckman investigator, on experiments using the Advanced Photon Source at Argonne National Laboratory. Their small-angle x ray-scattering work illuminates HDL assembly and transformation.

As significant as this work is for the study of cholesterol, it may be most notable for figuring out how such neat, discrete packages self-assemble. That is valuable because, in the real world, biophysicists are trying to use similarly shaped particles to study the structures of physically isolated membrane proteins.

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