Free Energy Profiles of Large Scale Protein Conformational Changes

The function of many enzymes requires a transformation between widely different conformational states. Often simulations of all-atom models are not capable of determining the transformation between experimentally known end states because of the large system size and wide range of these conformational changes. However, the characterization of such transition pathways using coarse-grained models can identify significant features such as free energy barriers. In this study we employed a Monte Carlo simulation framework where bond lengths and bond angles are preserved in order to generate an initial pathway along the change in RMSD connecting these end point conformations. Within this framework, rotatable dihedral bonds along the main chain and side chain serve as the effective degrees of freedom. We then sampled conformations for each of the intermediates along this pathway without bias. The resulting conformations were combined in order to calculate the free energy profiles for these conformational changes in different proteins. These profiles yield realistic free energy barriers and indicate the degree to which conformational change is coupled to ligand binding in these enzymes.View Large Image | View Hi-Res Image | Download PowerPoint Slide