Investigations on domain movements of N-acetyltransferase in nano scale

Molecular Dynamics simulations were performed on aminoglycoside N-acetyltransferase ((AAC) (2')-Ic) of Mycobacterium tuberculosis, to gain insight into enzyme flexibility and conformation around the ligand and acetyl-CoA binding sites in nano scale. Simulations were performed in water and methanol to further study the effect of solvation on the enzyme. AAC(2')-Ic of M. tuberculosis consists of negatively charged residues of aspartic and glutamic acids, which are believed to form a docking platform for the positively charged aminoglycosides. The acetyl-CoA binding site involves a wide groove surrounded by helices alphal, alpha3, alpha4 and strand beta4. Simulation results revealed the enzyme to be stable in water and the enzyme was found to be flexible around the docking platform (ligand binding site) with Asp 35, Asp 40 and Asp 179 exhibiting maximum movement. An interesting observation was the flexibility and conformational change at beta4, hydrophobic pocket of the acetyl-CoA binding site a prerequisite for catalysis to occur with Leu 95 exhibiting maximum displacement with a root mean square fluctuation of 0.18 nm. The enzyme was found to be very unstable in methanol with root mean square deviation not stabilizing even at 10 ns.