Abstract
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 ATVRLQp1Ap1'-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.
Original language | English (US) |
---|---|
Pages (from-to) | 747-757 |
Number of pages | 11 |
Journal | Proteins: Structure, Function and Genetics |
Volume | 57 |
Issue number | 4 |
DOIs | |
State | Published - Dec 1 2004 |
Keywords
- 3CL-PRO
- Anti-SARS-CoV drugs
- Coronavirus
- Main proteinase
- Protein modeling
ASJC Scopus subject areas
- Structural Biology
- Biochemistry
- Molecular Biology