title: Insight into the activity of SARS main protease: Molecular dynamics study of dimeric and monomeric form of enzyme.
abstract: The phenomenon that SARS coronavirus main protease (SARS M(pro)) dimer is the main functional form has been confirmed by experiment. However, because of the absence of structural information of the monomer, the reasons for this remain unknown. To investigate it, two molecular dynamics (MD) simulations in water for dimer and monomer models have been carried out, using the crystal structure of protomer A of the dimer as the starting structure for the monomer. During the MD simulation of dimer, three interest phenomena of protomer A have been observed: (i) the distance between NE2 of His41 and SG of Cys145 averages 3.72 A, which agrees well with the experimental observations made by X-ray crystallography; (ii) His163 and Glu166 form the "tooth" conformational properties, resulting in the specificity for glutamine at substrate P1 site; and (iii) the substrate-binding pocket formed by loop 140-146 and loop 184-197 is large enough to accommodate the substrate analog. However, during the MD simulation of the monomer complex, the three structural characteristics are all absent, which results directly in the inactivation of the monomer. Throughout the MD simulation of the dimer, the N-terminus of protomer B forms stable hydrogen bonds with Phe140 and Glu166, through which His163, Glu166, and loop 140-146 are kept active form. Furthermore, a water-bridge has been found between the N-terminus of protomer B and Gly170, which stabilizes His172 and avoids it moving toward Tyr161 to disrupt the H-bond between Tyr161 and His163, stabilizing the conformation of His163. The interactions between the N-terminus and another monomer maintain the activity of dimer.
authors.affiliation: Institute of Environmental Pollution and Health, School of Environmental and Chemical Engineering, Shanghai University, Shanghai 200072, China.
authors.forename: Kewen
authors.initials: K
authors.lastname: Zheng
authors.forename: Guozheng
authors.initials: G
authors.lastname: Ma
authors.forename: Jinming
authors.initials: J
authors.lastname: Zhou
authors.forename: Min
authors.initials: M
authors.lastname: Zen
authors.forename: Wenna
authors.initials: W
authors.lastname: Zhao
authors.forename: Yongjun
authors.initials: Y
authors.lastname: Jiang
authors.forename: Qingsen
authors.initials: Q
authors.lastname: Yu
authors.forename: Jialiang
authors.initials: J
authors.lastname: Feng
mesh_terms: D020134:Catalytic Domain; D003198:Computer Simulation; D000086782:Coronavirus 3C Proteases; D003546:Cysteine Endopeptidases / Q000737:chemistry / Q000378:metabolism*; D019281:Dimerization; D006860:Hydrogen Bonding; D006868:Hydrolysis; D008956:Models, Chemical; D008958:Models, Molecular; D011480:Protease Inhibitors / Q000494:pharmacology; D011487:Protein Conformation; D025941:Protein Interaction Mapping; D045473:Severe acute respiratory syndrome-related coronavirus / Q000201:enzymology*; D013329:Structure-Activity Relationship; D013379:Substrate Specificity; D014764:Viral Proteins / Q000737:chemistry / Q000378:metabolism*; D014867:Water
chemical_list: D011480:Protease Inhibitors; D014764:Viral Proteins; D014867:Water; C000706207:3C-like protease, SARS coronavirus; D003546:Cysteine Endopeptidases; D000086782:Coronavirus 3C Proteases