Three‐dimensional model of a substrate‐bound SARS chymotrypsin‐like cysteine proteinase predicted by multiple molecular dynamics simulations: Catalytic efficiency regulated by substrate binding

Pang, Yuan‐Ping

Severe acute respiratory syndrome (SARS) is a contagious and deadly disease caused by a new coronavirus. The protein sequence of the chymotrypsin‐like cysteine proteinase (CCP) responsible for SARS viral replication has been identified as a target for developing anti‐SARS drugs. Here, I report the ATVRLQ(p1)A(p1')‐bound CCP 3D model predicted by 420 different molecular dynamics simulations (2.0 ns for each simulation with a 1.0‐fs time step). This theoretical model was released at the Protein Data Bank (PDB; code: 1P76) before the release of the first X‐ray structure of CCP (PDB code: 1Q2W). In contrast to the catalytic dyad observed in X‐ray structures of CCP and other coronavirus cysteine proteinases, a catalytic triad comprising Asp187, His41, and Cys145 is found in the theoretical model of the substrate‐bound CCP. The simulations of the CCP complex suggest that substrate binding leads to the displacement of a water molecule entrapped by Asp187 and His41, thus converting the dyad to a more efficient catalytic triad. The CCP complex structure has an expanded active‐site pocket that is useful for anti‐SARS drug design. In addition, this work demonstrates that multiple molecular dynamics simulations are effective in correcting errors that result from low‐sequence‐identity homology modeling. Proteins 2004. © 2004 Wiley‐Liss, Inc.