Title: The Free Energy Reaction Path Theory of Reliable Protein Folding
Abstract: A growing number of experiments and simulations detect long-lived metastable and intermediate states in proteins, which suggests that protein folding does not always occur on funneled energy landscapes. We introduce a theoretical framework to understand folding in the presence of metastable and intermediate states by considering the statistics of protein conformational dynamics on rugged energy landscapes. Our analysis reveals that, even for the most frustrated proteins, reliable folding can occur on rugged energy landscapes and is sensitive to the rate that external parameters are adjusted to induce folding. When folding is reliable, there is always a well-defined reaction path leading to the native state. We test the predictions of our statistical analysis using simulations of a model protein. In the accompanying figure we plot the probability P to inhabit the native state after inducing folding by reducing the temperature at rate r. Reliable folding only occurs below a limiting rate that is correctly predicted by theory (red line).