| Abstract
| - More than a dozen proteins are known to be ultrafast folders. In addition to being fast, theirkinetics is unusual. Like traditional rate processes, fast folding proteins have activation barriers at lowtemperatures, but unlike traditional processes, they have negative activation energies at high temperatures.We develop a model of ultrafast folders that joins a macroscopic mass-action model with a microscopicenergy landscape description; we call it the Thruway Search Model. We find good agreement withexperimental rates and equilibria on 13 ultrafast folders. The observed folding rates are found to beproportional to the number of microscopic folding routes: fast-folding proteins have more parallel microscopicroutes on energy landscapes. At high temperatures, where traditional barriers are small, the remainingbottleneck is a search through denatured conformations to find thruway routes to the native state. Negativeactivation arises because increasing temperature expands the denatured ensemble, broadening the search,slowing the folding to the native state. We find that the upper estimate of the free energy barriers arepositive but small, as little as 0.5 kT.
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