Abstract
BackgroundSARS 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.ResultsThe one turn α-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.ConclusionMD 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.
Highlights
SARS coronavirus main proteinase (SARS CoVMpro) is an important enzyme for the replication of Severe Acute Respiratory Syndrome virus
We present the 2 ns conventional molecular dynamics (MD) simulation of the SARS CoVMpro complexed with the octapeptide and compare this to an uncomplexed SARS CoVMpro, with the purpose of investigating the amino acids in each subsite, and especially S3, which are crucial to increasing the substrate binding
This result indicated that the structure of the SARS CoVMpro and, in particular, the active site obtained from this research differed from the crystal structure
Summary
SARS coronavirus main proteinase (SARS CoVMpro) is an important enzyme for the replication of Severe Acute Respiratory Syndrome virus. Previous studies on substrate specificity indicated that the active site, including the binding site, of the SARS CoVMpro could bind to a substrate containing 8 amino acids These positions in the octapeptide were termed P5-P4-P3-P2-P1-P1'-P2'-P3' and the sequence Ser-Ala-Val-Leu-Gln-Ser-Gly-Phe. These positions in the octapeptide were termed P5-P4-P3-P2-P1-P1'-P2'-P3' and the sequence Ser-Ala-Val-Leu-Gln-Ser-Gly-Phe This sequence is optimal for the proteinase from Transmissible Gastro Enteritis Virus (TGEV), but it is unsuitable for SARS CoVMpro [7]. At the P3 position these octapeptides contained either a long chain positive charge or an aliphatic hydrophobic amino acid This was proposed to prove that the P3Lys is a significant amino acid for binding in the S3 subsite of the SARS CoVMpro.
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