The Mechanism of Population Shifting among Transition States of Adenylate Kinase

Abstract

The rearrangement of LID and NMP domains of adenylate kinase (ADK) in solution is important to ADK's catalytic function. To study the mechanism of the phosphotransferase reaction conduct by ADK, we applied a multi-basin structure-based (SMOG) coarse-grained model with targeted molecular dynamics (MD) protocols in the MD simulation of apo-ADK. The MD trajectories produce substantial ensembles that help to explore the transition states and pathways between the open and the closed states of ADK. We classified all observed states into 5 to 7 clusters using RMSD among structures as the metric for ‘k-means’ clustering. The comparisons of the x-ray solutionscattering pattern of ADK with that calculated from representative structures of each cluster were used to characterize the experimental ensembles under different solution conditions. Combined with the transfer rate between clusters, these analyses provide a framework for understanding the possible allosteric pathway underlying the catalytic function of this important enzyme.