title: Mechanistic insight into the functional transition of the enzyme guanylate kinase induced by a single mutation.
abstract: Dramatic functional changes of enzyme usually require scores of alterations in amino acid sequence. However, in the case of guanylate kinase (GK), the functional novelty is induced by a single (S→P) mutation, leading to the functional transition of the enzyme from a phosphoryl transfer kinase into a phosphorprotein interaction domain. Here, by using molecular dynamic (MD) and metadynamics simulations, we provide a comprehensive description of the conformational transitions of the enzyme after mutating serine to proline. Our results suggest that the serine plays a crucial role in maintaining the closed conformation of wild-type GK and the GMP recognition. On the contrary, the S→P mutant exhibits a stable open conformation and loses the ability of ligand binding, which explains its functional transition from the GK enzyme to the GK domain. Furthermore, the free energy profiles (FEPs) obtained by metadymanics clearly demonstrate that the open-closed conformational transition in WT GK is positive correlated with the process of GMP binding, indicating the GMP-induced closing motion of GK enzyme, which is not observed in the mutant. In addition, the FEPs show that the S→P mutation can also leads to the mis-recognition of GMP, explaining the vanishing of catalytic activity of the mutant.
authors: State Key Laboratory of Molecular Reaction Dynamics, Dalian Institute of Chemical Physics, Chinese Academy of Sciences, 457 Zhongshan Rd, Dalian 116023, P.R. China.
authors: Yuebin
authors: Y
authors: Zhang
authors: Department of Geriatrics, Shengjing Hospital, China Medical University, 36 Sanhao Street, Heping, Shenyang 110004, P. R. China.
authors: Huiyan
authors: H
authors: Niu
authors: State Key Laboratory of Molecular Reaction Dynamics, Dalian Institute of Chemical Physics, Chinese Academy of Sciences, 457 Zhongshan Rd, Dalian 116023, P.R. China.
authors: Yan
authors: Y
authors: Li
authors: State Key Laboratory of Molecular Reaction Dynamics, Dalian Institute of Chemical Physics, Chinese Academy of Sciences, 457 Zhongshan Rd, Dalian 116023, P.R. China.
authors: Huiying
authors: H
authors: Chu
authors: State Key Laboratory of Molecular Reaction Dynamics, Dalian Institute of Chemical Physics, Chinese Academy of Sciences, 457 Zhongshan Rd, Dalian 116023, P.R. China.
authors: Hujun
authors: H
authors: Shen
authors: State Key Laboratory of Molecular Reaction Dynamics, Dalian Institute of Chemical Physics, Chinese Academy of Sciences, 457 Zhongshan Rd, Dalian 116023, P.R. China.
authors: Dinglin
authors: D
authors: Zhang
authors: State Key Laboratory of Molecular Reaction Dynamics, Dalian Institute of Chemical Physics, Chinese Academy of Sciences, 457 Zhongshan Rd, Dalian 116023, P.R. China.
authors: Guohui
authors: G
authors: Li
mesh_terms: D004789:Enzyme Activation; D006157:Guanosine Monophosphate / Q000378:metabolism; D051528:Guanylate Kinases / Q000737:chemistry* / Q000235:genetics* / Q000378:metabolism; D008958:Models, Molecular; D056004:Molecular Dynamics Simulation; D009154:Mutation; D011487:Protein Conformation
chemical_list: D006157:Guanosine Monophosphate; D051528:Guanylate Kinases