title: 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.
authors.affiliation: Tianjin Normal University and Tianjin Institute of Bioinformatics and Drug Discovery, Tianjin 300074, China.
authors.forename: Qi-Shi
authors.initials: QS
authors.lastname: Du
authors.forename: Shu-Qing
authors.initials: SQ
authors.lastname: Wang
authors.forename: Yu
authors.initials: Y
authors.lastname: Zhu
authors.forename: Dong-Qing
authors.initials: DQ
authors.lastname: Wei
authors.forename: Hong
authors.initials: H
authors.lastname: Guo
authors.forename: Suzanne
authors.initials: S
authors.lastname: Sirois
authors.forename: Kuo-Chen
authors.initials: KC
authors.lastname: Chou
mesh_terms: D000595:Amino Acid Sequence; D001665:Binding Sites; D003198:Computer Simulation; D000086782:Coronavirus 3C Proteases; D003545:Cysteine / Q000737:chemistry; D003546:Cysteine Endopeptidases / Q000737:chemistry / Q000378:metabolism*; D015195:Drug Design; D005973:Glutamine / Q000737:chemistry; D006639:Histidine / Q000737:chemistry; D006860:Hydrogen Bonding; D008958:Models, Molecular; D008967:Molecular Biology; D015394:Molecular Structure; D010455:Peptides / Q000737:chemistry*; D011487:Protein Conformation; D017434:Protein Structure, Tertiary; D011789:Quantum Theory; D045473:Severe acute respiratory syndrome-related coronavirus / Q000737:chemistry* / Q000302:isolation & purification / Q000378:metabolism*; D012694:Serine / Q000737:chemistry; D045169:Severe Acute Respiratory Syndrome / Q000821:virology*; D055672:Static Electricity
chemical_list: D010455:Peptides; D005973:Glutamine; D012694:Serine; D006639:Histidine; D003546:Cysteine Endopeptidases; D000086782:Coronavirus 3C Proteases; D003545:Cysteine