This un-edited manuscript has been accepted for publication in Biophysical Journal and is freely available on BioFAST at www.biophysj.org. The final copyedited version of the paper may be found at www.biophysj.org.

Conformational heterogeneity in proteins is known to often be the key to their function. We present a coarse grained model to explore the interplay between protein structure, folding and function which is applicable to allosteric or non-allosteric proteins. We employ the model to study the detailed mechanism of the reversible conformational transition of Adenylate Kinase (AKE) between the open to the closed conformation, a reaction that is crucial to the protein's catalytic function. We directly observe high strain energy which appears to be correlated with localized unfolding during the functional transition. This work also demonstrates that competing native interactions from the open and closed form can account for the large conformational transitions in AKE. We further characterize the conformational transitions with a new measure ΦFunc, and demonstrate that local unfolding may be due, in part, to competing intra-protein interactions.

pre-existing equilibrium, dynamic population shift “Teaser”: A discussion of current articles revealing conformational changes upon protein-protein binding shows there is increasing experimental data supporting the hypothesis that unbound proteins exist in multiple conformations. Summary Motions related to protein–protein binding events can be surveyed from the perspective of the Database of Macromolecular Movements. There are a number of alternate conceptual models that describe these events, particularly induced fit and pre-existing equilibrium. There is evidence for both alternatives from recent studies of conformational change. However, there is increasing support for the pre-existing equilibrium model, whereby proteins are found to simultaneously exist in populations of diverse conformations.