Molecular Dynamics Simulation Study on the Mechanism of the Inhibition of ATP Hydrolysis with Inhibitors in Human Papillomavirus Type 18 E1 Helicase

The biphenylsulfonacetic acid and its derivatives were found to inhibit ATP hydrolysis by an allosteric mechanism involving tyrosine 486 of HPV6 E1 Helicase as well as tyrosine 492 of HPV 18 E1. A theoretical study on the binding conformations and allosteric function of these inhibitors has been carried out using docking analysis and molecular dynamics (MD) simulation. The appropriate binding orientations and conformations of the (biphenyl-4-ylsulfonyl) acetic acid interacting with HPV 18 E1 were revealed by the docking study. The MD simulation results obtained from NAMD showed that the binding of (biphenyl-4-ylsulfonyl) acetic acid at the site of Tyr492 was stabilizing around the Lys490 of HPV18 E1, the active site of its ATP hydrolysis. And the protein structure near its predicted allosteric and active sites of HPV 18 E1 has been altered after the binding of the inhibitor to the protein E1 with the different second structure type and length, suggesting that this compound could change the structure conformation near the active center of E1, through which exerts its enzyme-inhibiting function. A series of biphenylsulfonacetic acid derivatives, the reported HPV18 E1 inhibitors, have been then analyzed by docking study. The results revealed that all these compounds could stably bind to the protein with a good binding free energy, suggesting these derivatives could exert a similar allosteric effect on the E1 protein. Taken together, these theoretical results can offer useful references for understanding the mechanisms of allosteric effect of these compounds and directing the molecular design of this kind of inhibitor with improved activity.