In silico Analysis of Novel Mutation Ala102Pro targeting pncA Gene of M.

This study reports on the structural and functional basis of pyrazinamide (PZA) resistance conferred by a novel mutation Ala102Pro in pncA gene as sequenced from a PZA resistant Mycobacterium tuberculosis strain. Molecular modeling studies of Wild Type (WT) and Mutant Type (MT) of Pyrazinamidase (PZase) showed the mutation at Ala102Pro does not impact on the conformation of the protein. However, the docking studies infer that MT has a higher inhibitory constant (Ki-990.0m) compared to WT (Ki-822.42m), which is indicative of drug resistance in MT. Furthermore, molecular interaction studies also reveal that WT forms 4 hydrogen bonds involved in PZA-WT inhibitory interactions, whereas, in case of MT, it formed 5 hydrogen bonds with PZA. However, Ala102 in WT was found to be less fluctuating and more stable in molecular dynamics simulation when compared to Pro102 in MT which was highly fluctuating and unstable. This implies that Ala102 shall be a key residue involved in PZA inhibitory interactions. Moreover, MT does not show hydrogen bonding with PZA with Pro102 and also deviating in terms of PZA binding pose in comparison with WT. Hence, the observed deviations in terms of MT-PZA interactions shall be attributed to the drug resistance conferred.