On the role of cooperativity in funneled energy landscapes.

Abstract

The consistency of energy landscape theory predictions with available experimental data, as well as direct evidence from molecular simulations, have shown that protein folding mechanisms are largely determined by the contacts present in the native structure. As expected, native contacts are generally energetically favorable, however there are usually at least as many energetically favorable non-native pairs owing to the greater number of possible non-native interactions. This apparent frustration must therefore be reduced by the greater cooperativity of native interactions. In this work, we analyze the unbiased all-atom folding trajectories obtained by Shaw and co-workers, focusing on the unfolded state. By computing mutual cooperativities between contacts formed in the unfolded state, we are able to show that native contacts are largely more cooperative with each other than non-native contacts. Furthermore, we show that our analysis can determine the cooperative structures in the unfolded state and that native contacts can be more accurately predicted from the unfolded state trajectories than from residue contact frequencies in the unfolded state or from statistical pair potentials.