Polyprotein cleavage mechanism of SARS CoV Mpro and chemical modification of the octapeptide

Abstract

The cleavage mechanism of severe acute respiratory syndrome (SARS) coronavirus main proteinase (M(pro) or 3CL(pro)) 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 pi-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 CH(2) or CF(2). This leads to a break of the pi-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.

Fig. 1

A schematic drawing to illustrate the “distorted key” theory , : (a) the cleavage location in the octapeptide by protease is the peptide bond between R₁ and R_1′; (b) after chemical modification, the scissile peptide bond changes to a strong “hybrid peptide bond” and the cleavage is difficult. Adapted from Chou with permission.

Fig. 2

The energy-refined docked structure of the octapeptide NH₂—AVLQSGFR—COOH with SARS coronavirus main protease (SARS CoV M^pro).

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 M^pro. (b) The hydrogen bonds between NH₂—AVLQSGFR—COOH 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 M^pro.