Theoretical Insights into Catalytic Mechanism of Protein Arginine Methyltransferase 1 |
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| Authors: | Ruihan Zhang Xin Li Zhongjie Liang Kongkai Zhu Junyan Lu Xiangqian Kong Sisheng Ouyang Lin Li Yujun George Zheng Cheng Luo |
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| Institution: | 1. State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, China.; 2. Division of Nephrology, Shanghai Changzheng Hospital, Shanghai, China.; 3. Center for Systems Biology, Soochow University, Jiangsu, China.; 4. Department of Chemistry, Program of Molecular Basis of Diseases, Georgia State University, Atlanta, Georgia, United States of America.; Universität Stuttgart, Germany, |
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| Abstract: | Protein arginine methyltransferase 1 (PRMT1), the major arginine asymmetric dimethylation enzyme in mammals, is emerging as a potential drug target for cancer and cardiovascular disease. Understanding the catalytic mechanism of PRMT1 will facilitate inhibitor design. However, detailed mechanisms of the methyl transfer process and substrate deprotonation of PRMT1 remain unclear. In this study, we present a theoretical study on PRMT1 catalyzed arginine dimethylation by employing molecular dynamics (MD) simulation and quantum mechanics/molecular mechanics (QM/MM) calculation. Ternary complex models, composed of PRMT1, peptide substrate, and S-adenosyl-methionine (AdoMet) as cofactor, were constructed and verified by 30-ns MD simulation. The snapshots selected from the MD trajectory were applied for the QM/MM calculation. The typical SN2-favored transition states of the first and second methyl transfers were identified from the potential energy profile. Deprotonation of substrate arginine occurs immediately after methyl transfer, and the carboxylate group of E144 acts as proton acceptor. Furthermore, natural bond orbital analysis and electrostatic potential calculation showed that E144 facilitates the charge redistribution during the reaction and reduces the energy barrier. In this study, we propose the detailed mechanism of PRMT1-catalyzed asymmetric dimethylation, which increases insight on the small-molecule effectors design, and enables further investigations into the physiological function of this family. |
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