Folding PDZ2 Domain Using the Molecular Transfer Model.

Abstract

A major challenge in molecular simulations is to describe denaturant-dependent folding of proteins in order to make direct comparisons with in vitro experiments. We use the molecular transfer model (MTM), currently the only method that accomplishes this goal, albeit phenomenologically, to quantitatively describe urea-dependent folding of the PDZ2 domain, a protein that is important in molecular recognition and signaling. Experiments show that urea-dependent unfolding rates of the PDZ2 domain exhibit a downward curvature at high urea concentrations ([C]’s), which has been interpreted as indicating the presence of a sparsely populated high energy intermediate. Simulations using the MTM and a coarse-grained self-organized polymer (SOP) representation of PDZ2 are used to show that the intermediate (IEQ), which has some native-like character, is present in equilibrium both in the presence and absence of urea. The free energy profiles as a function of the structural overlap order parameter show that there are t...