"Computational models are also useful, but to understand the full dynamics of these large proteins, where a lot of the interesting biology takes place, we have to supplement them with more information," he said.
That information comes from direct coupling analysis (DCA), a statistical tool developed by Morcos and Onuchic with colleagues at the University of California, San Diego, and the Pierre and Marie Curie University. DCA looks at the genetic roots of proteins to see how amino acids the "beads" in the unfolded protein strands -- co-evolved to influence the way a protein folds. Each bead carries an intrinsic energy that contributes to the strand's distinct energy landscape, which dictates how it folds into its functional state.
Even after they fold, proteins are in perpetual motion, acting as catalysts for countless bodily functions. They can combine into larger molecular machines that grab other molecules, "walk" cargoes within a cell or cause muscles to contract.
One such biomachine is FtsH, a membrane-bound molecule in E. coli made of six protein copies that form two connected hexagonal rings. The molecule attracts and degrades misfolded proteins and other cellular detritus, pulling them in through one ring, which closes like the shutter of a camera and traps the proteins. They are cut apart as they exit through the other ring.
Through molecular simulations using structure-based models and the discovery via DCA of likely couplings in the genetic source of the proteins, the Rice team found evidence to support the hypothesis of a "paddling" mechanism in the molecule that Morcos described as a collapse of the two rings once trash found its way inside.
"First the ring pore closes to grab the protein; then the molecule flattens," he said. "Then when the motor is flat, the ring
|Contact: David Ruth|