Protein–Drug Interactions with Effective Polarizationin Polarizable Water: Oxime Unbinding from AChE Gorge.

Despitethe fact that polarizability of water is different in thebulk and in protein, simulations of protein–ligand complexesare mostly carried out in nonpolarizable water media. We present oxime(HI-6) unbinding from the active site gorge of AChE, known to be stronglyinfluenced by intermolecular cation-π, hydrogen bridge (HB)and water bridge (WB) interactions and by molecular simulations witheffective polarization in polarizable mean-field model of TIP3P water.Enabled by the recent availability of a method of obtaining microkineticsof rare events, we set out to investigate the rate constants of unbindingtransitions from one basin to the other through a combination of metadynamicsand hyperdynamics simulations. The results underpin the importanceof electronic polarization effects on the pathways, potential of meanforce, rate constants, and HB and WB dynamics of unbinding transitionsof a drug molecule ligated to protein interior. The method is alsoapplicable to unravel the binding mechanisms. [ABSTRACT FROM AUTHOR]