Protein folding kinetics and energy landscapes

5 problems

• Molecular mechanism of secondary nucleation on amyloid fibrils

  Open

  Some proteins stack into long fibers called amyloids, and the surface of an existing fiber speeds up the birth of new ones, which drives the self-amplifying aggregation seen in neurodegenerative disease. How the fiber surface does this, molecule by molecule, is unknown.

• Does the GroEL chaperonin actively speed folding or only isolate?

  Contested

  The bacterial machine GroEL encloses a misfolded protein in a cage, burns ATP and releases it, and many proteins fold only with its help. Whether it merely shields the protein from clumping or actively unfolds trapped states so that they can refold is disputed.

• Measure the folding-to-glass temperature ratio of a real protein

  Open

  Energy landscape theory says a protein folds reliably only if the pull toward its native shape beats the roughness of its energy surface, meaning the many traps a chain can fall into. The roughness has been estimated at a few times the thermal energy, but the ratio of two temperatures that decides foldability has not been measured for a natural protein.

• Predict a protein's folding rate from its sequence alone

  Open

  Small proteins fold at rates that differ by roughly a factor of a hundred million, and sequence-based formulas reproduce the trend only on proteins they were fitted to. The goal is a sequence-only predictor whose accuracy holds on proteins it has never seen.

• What sets the folding speed limit and internal friction

  Partially resolved

  The fastest proteins fold in about a microsecond, and theory and experiment suggest a floor of roughly N/100 microseconds for a chain of N amino acids. The question is which physical process sets this floor: the chain moving through water, or friction inside the chain itself.