doi:10.1016/j.peptides.2004.06.018
Copyright © 2004 Elsevier Inc. All rights reserved.
Polyprotein cleavage mechanism of SARS CoV Mpro and chemical modification of the octapeptide
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Qi-Shi Dua, b, Shu-Qing Wanga, Yu Zhua, Dong-Qing Weia, b, c, Hong Guod, Suzanne Siroisb and Kuo-Chen Choua, e, f, 
, 
aTianjin Normal University and Tianjin Institute of Bioinformatics and Drug Discovery (TIBDD), Tianjin 300074, China
bInstitut Technologique de Montreal, Suite 168, 5253 Boul. Decarie, Montreal, Que., Canada H3W 3C3
cCenter For Research in Molecular Modeling (CERMM), Concordia University, Montreal, Canada
dUniversity of Tennessee, Department of Biochemistry, Cell and Molecular Biology, Knoxville, TN 37996-0840, USA
eInstitute of Image Processing and Pattern Recognition, Shanghai Jiaotong University, Shanghai 200030, China
fGordon Life Science Institute, San Diego, CA 92130, USA
Received 1 May 2004;
revised 18 June 2004;
accepted 22 June 2004.
Available online 31 July 2004.
Abstract
The cleavage mechanism of severe acute respiratory syndrome (SARS) coronavirus main proteinase (Mpro or 3CLpro) for the octapeptide AVLQSGFR is studied using molecular mechanics (MM) and quantum mechanics (QM). The catalytic dyad His-41 and Cys-145 in the active pocket between domain I and II seem to polarize the π-electron density of the peptide bond between Gln and Ser in the octapeptide, leading to an increase of positive charge on C(CO) of Gln and negative charge on N(NH) of Ser. The possibility of enhancing the chemical bond between Gln and Ser based on the “distorted key” theory [Anal. Biochem. 233 (1996) 1] is examined. The scissile peptide bond between Gln and Ser is found to be solidified through “hybrid peptide bond” by changing the carbonyl group CO of Gln to CH2 or CF2. This leads to a break of the π-bond system for the peptide bond, making the octapeptide (AVLQSGFR) a “distorted key” and a potential starting system for the design of anti SARS drugs.
Keywords: SARS; Coronavirus main proteinase; Inhibitor; Distorted key theory; Drug design; Octapeptide; KZ7088
Abbreviations: SARS, severe acute respiratory syndrome; CoV, coronavirus; Mpro, main proteinase
Fig. 1. A schematic drawing to illustrate the “distorted key” theory [12] and [13]: (a) the cleavage location in the octapeptide by protease is the peptide bond between R1 and R1′; (b) after chemical modification, the scissile peptide bond changes to a strong “hybrid peptide bond” and the cleavage is difficult. Adapted from Chou [12] with permission.
Fig. 2. The energy-refined docked structure of the octapeptide NH2
AVLQSGFRCOOH with SARS coronavirus main protease (SARS CoV Mpro).
Fig. 3. (a) The catalytic dyad His-41 and Cys-145 are located in the active cleft between domain I and domain II of SARS CoV Mpro. (b) The hydrogen bonds between NH2AVLQSGFRCOOH and the surrounding amino acid residue of the enzyme.
Fig. 4. Electron density counter map of peptide bond Gln–Ser in gaseous phase on the π-plane consisting of carbonyl C and O of Gln and N(NH) of Ser.
Fig. 5. The counter map of electron density difference of peptide bond Gln–Ser in the octapeptide AVLQSGFR obtained by subtracting the electronic density in gaseous phase from the electronic density in background charges of SARS CoV Mpro.
Table 1.
Division of amino acid residues in the active cleft of SARS CoV Mpro, total 62 amino acid residues and 953 atoms are included
Table 2.
Atomic charges of amino acid His-41in SARS CoV Mpro
Table 3.
Chemical reaction energy of the octapeptide cleavage in gaseous phasea
a 1 Hartree = 2625.5 kJ/mol.
Table 4.
Atomic charges and coordinates of six atoms on the both sides of peptide bond Gln–Ser in the octapeptide
a Atomic charges in the gaseous phase.
b Atomic charges in SARS CoV M
pro background charges.
Table 5.
Atomic charges of the six atoms on two sides of peptide bond Gln–Ser after chemical modification
a Atomic charges in gaseous phase.
b Atomic charges in SARS CoV M
pro background charges.
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