A computational analysis of SARS cysteine proteinase-octapeptide substrate interaction: implication for structure and active site binding mechanism.
BACKGROUND
SARS coronavirus main proteinase (SARS CoVMpro) is an important enzyme for the replication of Severe Acute Respiratory Syndrome virus. The active site region of SARS CoVMpro is divided into 8 subsites. Understanding the binding mode of SARS CoVMpro with a specific substrate is useful and contributes to structural-based drug design. The purpose of this research is to investigate the binding mode between the SARS CoVMpro and two octapeptides, especially in the region of the S3 subsite, through a molecular docking and molecular dynamics (MD) simulation approach.


RESULTS
The one turn alpha-helix chain (residues 47-54) of the SARS CoVMpro was directly involved in the induced-fit model of the enzyme-substrate complex. The S3 subsite of the enzyme had a negatively charged region due to the presence of Glu47. During MD simulations, Glu47 of the enzyme was shown to play a key role in electrostatic bonding with the P3Lys of the octapeptide.


CONCLUSIONS
MD simulations were carried out on the SARS CoVMpro-octapeptide complex. The hypothesis proposed that Glu47 of SARS CoVMpro is an important residue in the S3 subsite and is involved in binding with P3Lys of the octapeptide.
Phakthanakanok
Krongsakda
K
Division of Biochemical Technology, School of Bioresources and Technology, King Mongkut's University of Technology Thonburi, Bangkok, Thailand. s7500802@st.kmutt.ac.th
Ratanakhanokchai
Khanok
K
Kyu
Khin Lay
KL
Sompornpisut
Pornthep
P
Watts
Aaron
A
Pinitglang
Surapong
S
D001665:Binding Sites; D020134:Catalytic Domain; D019295:Computational Biology / Q000379:methods*; D000086782:Coronavirus 3C Proteases; D003546:Cysteine Endopeptidases / Q000737:chemistry* / Q000378:metabolism; D015853:Cysteine Proteinase Inhibitors / Q000737:chemistry* / Q000378:metabolism; D006860:Hydrogen Bonding; D008958:Models, Molecular; D009842:Oligopeptides / Q000737:chemistry* / Q000378:metabolism; D011487:Protein Conformation; D045473:Severe acute respiratory syndrome-related coronavirus / Q000201:enzymology* / Q000378:metabolism; D013329:Structure-Activity Relationship; D013379:Substrate Specificity; D014764:Viral Proteins / Q000737:chemistry* / Q000378:metabolism
D015853:Cysteine Proteinase Inhibitors; D009842:Oligopeptides; D014764:Viral Proteins; D003546:Cysteine Endopeptidases; D000086782:Coronavirus 3C Proteases