Exploring the top of the protein folding funnel by experiment.

While there have been impressive advances in understanding protein folding over the past few decades, we are still far from the goal of solving the protein folding problem: predicting the folding pathway and final structure entirely from the amino acid sequence. One reason for this shortcoming may be the lack of understanding of the complexity of the unfolded state before folding and earliest steps in the process. Recent technological advances and applications of cutting edge techniques in novel ways have begun to reveal this complexity. Comparing the kinetics with recent molecular dynamics simulations on the microsecond timescale may lead to more detailed and predictive folding models.