Misfolded proteins play a key role in Alzheimer's disease

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Rice University physicists have unveiled an innovative way of finding out how proteins get their shape based on how they unfold when pulled apart. The experimental method could be of widespread use in the field of protein folding science, which has grown dramatically in the past decade, due in part to the discovery that misfolded proteins play a key role in diseases like Alzheimer's and Parkinson's.

If DNA is the blueprint for life, then proteins are the machines built from those blueprints. All living cells produce proteins by stringing together strands of amino acids based on the sequences of their DNA. Proteins are created in linear chains, like strands of pearls, with each amino acid representing a bead on the strand. However, knowing the order of the amino acids in the strand gives no clue about how a protein functions. That's because every protein folds into a three-dimensional shape within about one second of being made, and it is this shape that dictates the protein's function.

At the halfway point between it's folded and unfolded state, a protein is like a rollercoaster balanced at the crest of the highest hill on the track. Like the rollercoaster, the protein requires a certain amount of energy to make it over the hill and wind its course to a final resting place -- its folded state. If it lacks the energy to clear the hill, it will slide back into a partially folded or misfolded state.

Scientists conducted experiments on a protein named Titin. The Titin piece, dubbed I27, contains 89 amino acids. Harris suspended thousands of intact, folded I27s in a dilute saline solution and let the solution sit long enough for the proteins to become stuck to the bottom of the sample dish. The needle from an atomic force microscope (AFM) was repeatedly dipped into the solution. The tip of the AFM operates much like a phonograph needle. The AFM needle is on the end of a cantilever arm that bobs up and down over the sample. The tip of the AFM needle is just a few atoms wide. Bobbing down, it randomly grabbed I27s that were pulled into their string-like, unfolded shape as the needle rose.

Harris measured the force exerted on the cantilever arm each time an I27 was unfolded. To get the energy maps, he wrote software incorporating a statistical mechanics equation called the "Jarzynski equality." The equation related the non-equilibrium energy from the unfolding events to the equilibrium profiles along the trajectory from the folded to the unfolded state. Kiang said the software, and the use of the Jarzynski equality, makes the new method unique and useful.

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