Glycolipids like
phosphatidylinositol hexamannosides (PIM
6
) and lipoglycans,
such as lipomannan (LM) and lipoarabinomannan
(LAM), play crucial roles in virulence, survival, and antibiotic resistance
of various mycobacterial species. Phosphatidyl-myo-inositol mannosyltransferase
A (PimA) catalyzes the transfer of the mannose moiety (M) from GDP-mannose
(GDPM) to phosphatidyl-myo-inositol (PI) to synthesize GDP and phosphatidyl-myo-inositol
monomannoside (PIM). This PIM is mannosylated, acylated, and further
modified to give rise to the higher PIMs, LM, and LAM. It is yet to
be known how PI, PIM, PI-GDPM, and PIM-GDP interact with PimA. Here,
we report the docked structures of PI and PIM to understand how the
substrates and the products interact with PimA. Using molecular dynamics
(MD) simulations for 300 ns, we have investigated how various ligand-bound
conformations change the dynamics of PimA. Our studies demonstrated
the “open to closed” motions of PimA. We observed that
PimA is least dynamic when bound to both GDPM and PI. MD simulations
indicated that the loop residues 59–70 and the α-helical
residues 73–86 of PimA play important roles while interacting
with both PI and PIM. MD analyses also suggested that the residues
Y9, P59, R68, L69, N97, R196, R201, K202, and R228 of PimA play significant
roles in the mannose transfer reaction. Overall, docking studies and
MD simulations provide crucial insights to design future therapeutic
drugs against mycobacterial PimA.