Jinzhi Tan a , b , † , Koen H.G. Verschueren b , † , Kanchan Anand b , Jianhua Shen a , Maojun Yang b , Yechun Xu a , Zihe Rao c , Janna Bigalke b , Burkhard Heisen b , Jeroen R. Mesters b , Kaixian Chen a , Xu Shen a , Hualiang Jiang a , * , Rolf Hilgenfeld b , *
23 September 2005
SARS-CoV Mpro, molecular dynamics simulation, new crystal forms, multiple X-ray structures, conformational flexibility, CoV, coronavirus, MD, molecular dynamics, Mpro, main proteinase, RMS, root-mean-square, RMSD, root-mean-square deviation, RMSF, root-mean-square fluctuation, SARS, severe acute respiratory syndrome
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.