title: The Atomistic Mechanism of Conformational Transition of Adenylate Kinase Investigated by Lorentzian Structure-Based Potential.
abstract: We present a new all-atom structure-based method to study protein conformational transitions using Lorentzian attractive interactions based on native structures. The variability of each native contact is estimated based on evolutionary information using a machine learning method. To test the validity of this approach, we have investigated the conformational transition of adenylate kinase (ADK). The intrinsic boundedness of the Lorentzian attractive interactions facilitated frequent conformational transitions, and consequently we were able to observe more than 1000 structural interconversions between the open and closed states of ADK out of a total of 6 μs MD simulations. ADK has three domains: the nucleoside monophosphate (NMP) binding domain, the LID-domain, and the CORE domain, which catalyze the interconversion between ATP and ADP. We identified two transition states: a more frequent LID-closed-NMP-open (TS1) state and a less frequent LID-open-NMP-closed (TS2) state. The transition was found to be symmetric in both directions via TS1. We also obtained an off-pathway metastable state that was previously observed with physics-based all-atom simulations but not with coarse-grained models. In the metastable state, the LID domain was slightly twisted and formed contacts with the NMP domain. Our model correctly identified a total of 14 out of the top 16 residues with highest fluctuation by NMR experiment, thus showing excellent agreement with experimental NMR relaxation data and overwhelmingly better results than existing models.
authors.affiliation: School of Computational Sciences, Korea Institute for Advanced Study , Dongdaemun-gu, Seoul 130-722, Korea.|Laboratory of Computational Biology, National Heart, Lung, and Blood Institute, National Institutes of Health , Bethesda, Maryland 20852, United States.
authors.forename: Juyong
authors.initials: J
authors.lastname: Lee
authors.affiliation: Center for In Silico Protein Science, Korea Institute for Advanced Study , Dongdaemun-gu, Seoul 130-722, Korea.|Center for Advanced Computation, Korea Institute for Advanced Study , Dongdaemun-gu, Seoul 130-722, Korea.
authors.forename: Keehyoung
authors.initials: K
authors.lastname: Joo
authors.affiliation: Laboratory of Computational Biology, National Heart, Lung, and Blood Institute, National Institutes of Health , Bethesda, Maryland 20852, United States.
authors.forename: Bernard R
authors.initials: BR
authors.lastname: Brooks
authors.affiliation: School of Computational Sciences, Korea Institute for Advanced Study , Dongdaemun-gu, Seoul 130-722, Korea.|Center for In Silico Protein Science, Korea Institute for Advanced Study , Dongdaemun-gu, Seoul 130-722, Korea.
authors.forename: Jooyoung
authors.initials: J
authors.lastname: Lee
mesh_terms: D000263:Adenylate Kinase / Q000737:chemistry* / Q000378:metabolism; D056004:Molecular Dynamics Simulation; D019906:Nuclear Magnetic Resonance, Biomolecular; D011487:Protein Conformation
chemical_list: D000263:Adenylate Kinase