Modeling the Open-to-closed Transition of Adenylate Kinase: All-atom Molecular Dynamics Simulations and a Double-Well Network Model

Abstract

An intrinsic property of protein is the ability to undergo conformational changes upon ligand binding. In this work, we study Adenylate Kinase (AKE), an important enzyme controlling the balance of ATP in prokaryotic cells. X-ray crystallography indicates that AKE has two distinct conformations, open and closed, depending on whether it is bound with substrates (ATP and AMP). Conformation difference in AKE can be determined by the relative position of two separate domains, the lid domain and the NMP binding domain, to the core. In this work, all-atom molecular dynamics (MD) simulations and coarse-grained modeling are used to elucidate the effects of ligand binding on AKE conformation. Results based on four 100ns all-atom trajectories indicate that ATP binding induced the closing of lid domain and suggest that the relative population between closed to open structure is increased. The closing of NMP binding domain, however, is found to be more specific and may require a timescale longer than 100ns to close. The mechanical property of a hinge region is found to correlate with lid closing; residues in this region may be mutated to alter the rate of conformational change and hence enzyme catalysis. This prediction agrees well with the results of recent single molecule experiments. Using a double-well network coarse-grained model, multiple pathways of open-to-closed transition can be found. Motions of lid-domain and NMP binding domain are not concerted and may be treated as two distinct events. This picture is different from the result of using elastic network model and agrees better with atomistic simulations. In addition to open-to-closed transition, solvation structures and intrinsic mechanical properties of AKE are also characterized to identify key residues that may control the conformational change of AKE from mechanical perspectives.