Interaction of antibiotic with aminoacyl tRNA synthetase active site : A molecular dynamics simulation study

Department of Chemistry, University of Kalyani, Kalyani-741 235, Nadia, West Bengal, India

E-mail : nilashisnandi@yahoo.com

Manuscript received 30 December 2016, accepted 06 April 2017

In the present work we present molecular dynamics simulation study of dimeric seryl tRNA synthetase bound with antibiotic molecule, SB 217452 that targets the active site of the bacterial enzyme and inhibits the protein biosynthesis. The interaction pattern within the active site of the enzyme is compared with the pattern in the active site of the enzyme with the adenylate to understand how the antibiotic acts as competitive inhibitor. Detailed analysis of the population of hydrogen bonds within the active sites bound with antibiotic and bound with adenylate have been carried out and compared. The results of the simulation show that the antibiotic develops hydrogen bonds, not present in the adenylate bound active site which leads to a tightly bound state of the antibiotic. Further, the conformation of the bound antibiotic is such that a reaction analogous to tRNA charging is impossible. The inhibitor molecule (SB 217452) which acts as a transition state analogue, has a higher affinity than the cognate substrate (or the related products) of aminoacylation. The SB 217452 binds to the enzyme more strongly by forming stable interactions with the enzyme. This tight-binding capacity of these transition state analogues allows them to be released slowly from the enzyme. The inhibitor SB 217452 resides within the active site of the enzyme relatively longer and acts as a competitive inhibitor. The present work, for the first time explains the antibiotic action of the SB 217452.