In the cell, the folding of proteins is facilitated by the presence of molecular chaperones. Chaperones appear to increase the yield of native proteins by protecting the polypeptide chains from aggregating during the folding process, and possibly by correcting misfolded structures. One of these chaperones is the GroEL chaperonin. GroEL function requires large conformational changes, which are induced by the binding of ATP and the co-chaperonin GroES. It remains unclear how ATP triggers these conformational changes and how these changes induce the (un) folding of proteins. We propose to elucidate two essential aspects of the GroEL cycle by several approaches based on molecular dynamics (MD) simulations. Our first objective is to show how ATP binding and hydrolysis induce the observed conformational transitions in GroEL. Hereto, we will perform MD free energy simulations to obtain the free energy differences among the structures involved, and employ a free energy component analysis to identify the key interactions. Our second objective is to examine if and how GroEL actively unfolds misfolded proteins. Hereto, we will "drive" the conformational transition of GroEL by applying an external force to simulate the changes in the time domain accessible to MD simulations. During the transition, the denatured protein will be simulated and extensively sampled We will track the unfolding process and determine the origin of the unfolding force by a detailed analysis of the protein substrate structures and from its interactions with GroEL.