Native and non-native interactions along protein folding and unfolding pathways.

Abstract

Gō-type models, which include only native contact interactions in the energy function, are being used increasingly to describe the protein folding reaction. To investigate the validity of such models, we determine the role of native and non-native interactions along folding and unfolding pathways. For this purpose, we use a molecular mechanics energy function with an implicit solvation model (an effective energy function or potential of mean force) that can be expressed in a pairwise decomposable form. We find that for the native state and a wide range of other configurations, the contact energy is an accurate description, in part due to the cancellation of non-zero contributions from more distant residues. However, significant errors in the energy are introduced for non-native structures if the energy is calculated from the native contacts alone. Non-native contacts tend to make a significant contribution, particularly for molten globules and collapsed states along the unfolding pathways. The implication of these results for the use of Gō-type models in studies of protein folding are discussed.