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74. Protein folded states are kinetic hubs.

G. R. Bowman and V. S. Pande. Proceedings of the National Academy of Sciences, USA (2010).

SUMMARY. By analyzing recent results from Folding@home, we have found a set of general properties emerging regarding how proteins fold. In particular, one of them comes as a surprise compared to previous models: the native state is a kinetic hub. This has implications for how we think about protein folding in general as well as applications of protein folding in biology and disease.

ABSTRACT. Understanding molecular kinetics, and particularly protein folding, is a classic grand challenge in molecular biophysics. Network models, such as Markov state models (MSMs), are one potential solution to this problem. MSMs have recently yielded quantitative agreement with experimentally derived structures and folding rates for specific systems, leaving them positioned to potentially provide a deeper understanding of molecular kinetics that can lead to experimentally testable hypotheses. Here we use existing MSMs for the villin headpiece and NTL9, which were constructed from atomistic simulations, to accomplish this goal. In addition, we provide simpler, humanly comprehensible networks that capture the essence of molecular kinetics and reproduce qualitative phenomena like the apparent two-state folding often seen in experiments. Together, these models show that protein dynamics are dominated by stochastic jumps between numerous metastable states and that proteins have heterogeneous unfolded states (many unfolded basins that interconvert more rapidly with the native state than with one another) yet often still appear two-state. Most importantly, we find that protein native states are hubs that can be reached quickly from any other state. However, metastability and a web of nonnative states slow the average folding rate. Experimental tests for these findings and their implications for other fields, like protein design, are also discussed.

75. A simple theory of protein folding kinetics.

V. S. Pande. Physical Review Letters, in press (2010).

SUMMARY. Recent work from detailed simulations of protein folding resulting from Folding@home have suggested some surprises and radical changes in how one conceptualizes protein folding kinetics. One of the more unusual aspects found in these simulations is the role of the native state as a kinetic hub (see paper #74). Here, we propose a new theory of protein folding that uses structural information in its kinetic equations and gives a much richer picture than previous theories. One key result is a prediction for what would cause the native state to be a kinetic hub and when one would see this effect (and in particular why it was not seen in simpler simulation studies previously).

ABSTRACT. We present a simple model of protein folding dynamics that captures key qualitative elements recently seen in all-atom simulations. The goals of this theory are to serve as a simple formalism for gaining deeper insight into the physical properties seen in detailed simulations as well as to serve as a model to easily compare why these simulations suggest a different kinetic mechanism than previous simple models. Specifically, we find that non-native contacts play a key role in determining the mechanism, which can shift dramatically as the energetic strength of non-native interactions is changed. For protein-like non-native interactions, our model finds that the native state is a kinetic hub, connecting the strength of relevant interactions directly to the nature of folding kinetics.