(308g) Multiscale Modeling And Simulation Of The Open-To-Close Transition Of Adenylate Kinase

Large-scale conformational changes of protein molecules are ubiquitous in regulating and activating biological process in the cell. Molecular level understanding of how protein molecules conduct conformational changes in responding to different environmental variables is thus critical in many areas of biotechnology and pharmaceutical industry. In this work, a multiscale approach is employed to study the open-to-closed transition of adenylate kinase (AKE) upon binding to ATP and the substrate. ATP is bound to AKE in the lid-domain and the substrate is bound to AKE in the NMP-binding domain. X-ray crystallography shows that both the lid-region and the NMP-binding domain are closed after AKE is bound with ATP and the substrate. Without the presence of ATP and the substrate, X-ray structure indicates that AKE has an open structure. To correlate the conformational dynamics of AKE with its enzymatic activity, various atomistic molecular dynamics (MD) simulations of AKE in explicit solvent were performed, with a total of 300 ns in trajectory length. The results indicate that without ATP and the substrate, AKE prefers the open structure in an aqueous environment. However, this behavior can be easily changed if negatively charged molecules are used to label AKE in these regions, since the catalytic core of AKE is positively charged in order to bind ATP and the substrate. Without the bound ligands, atomistic MD simulations indicate that AKE can open from the closed structure within 100 ns. In the presence of ATP, the lid-domain also closes within 100 ns, but the NMP-binding closes much slower, even in the presence of substrate. Based on these all-atom MD simulations, valuable insights into the pathways of the open-to-closed transition are also obtained, and a CG model that composes of a network of interconnected double-well potential was developed to characterize the structural transition of AKE. These results indicate that the double-well network CG model is robust in characterizing the structural transition of AKE and may be employed as a general means of studying protein structural transitions.