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pH-dependent conformational flexibility of the SARS-CoV main proteinase (M(pro)) dimer: molecular dynamics simulations and multiple X-ray structure analyses |
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| Authors: | Tan Jinzhi Verschueren Koen H G Anand Kanchan Shen Jianhua Yang Maojun Xu Yechun Rao Zihe Bigalke Janna Heisen Burkhard Mesters Jeroen R Chen Kaixian Shen Xu Jiang Hualiang Hilgenfeld Rolf |
| Institution: | Center for Drug Discovery and Design, State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Graduate School of Chinese Academy of Sciences, Chinese Academy of Sciences, Shanghai, China |
| Abstract: | The SARS coronavirus main proteinase (M(pro)) is a key enzyme in the processing of the viral polyproteins and thus an attractive target for the discovery of drugs directed against SARS. The enzyme has been shown by X-ray crystallography to undergo significant pH-dependent conformational changes. Here, we assess the conformational flexibility of the M(pro) by analysis of multiple crystal structures (including two new crystal forms) and by molecular dynamics (MD) calculations. The MD simulations take into account the different protonation states of two histidine residues in the substrate-binding site and explain the pH-activity profile of the enzyme. The low enzymatic activity of the M(pro) monomer and the need for dimerization are also discussed. |
| Keywords: | SARS-CoV Mpro molecular dynamics simulation new crystal forms multiple X-ray structures conformational flexibility |
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