Native states of fast-folding proteins are kinetic traps.

It has been suggested that the native state of a protein acts as a kinetic hub that can facilitate transitions between nonnative states. Using recently developed tools to quantify mediation probabilities ("hub scores"), we quantify hub-like behavior in atomic resolution trajectories for the first time. We use a data set of trajectory ensembles for 12 fast-folding proteins previously published by D. E. Shaw Research (Lindorff-Larsen, K.; et al. How Fast-Folding Proteins Fold. Science2011, 334, 517) with an aggregate simulation time of over 8.2 ms. We visualize the free-energy landscape of each molecule using configuration space networks, and show that dynamic quantities can be qualitatively understood from visual inspection of the networks. Modularity optimization is used to provide a parameter-free means of tessellating the network into a group of communities. Using hub scores, we find that the percentage of trajectories that are mediated by the native state is 31% when averaged over all molecules, and reaches a maximum of 52% for the homeodomain and chignolin. Furthermore, for these mediated transitions, we use Markov models to determine whether the native state acts as a facilitator for the transition, or as a trap (i.e., an off-pathway detour). Although instances of facilitation are found in 4 of the 12 molecules, we conclude that the native state acts primarily as a trap, which is consistent with the idea of a funnel-like landscape.