Configuration Flipping in Distal Pocket of Multidrug Transporter MexB Impacts the Efflux Inhibitory Mechanism.

Patra, Niladri; Roy, Rakesh Kumar

MexAB-OprM efflux pumps, found in Pseudomonas aeruginosa, plays a major role in drug resistance by extruding out drugs and antibiotic molecules from cells. Inhibitors are used to cease the potency of the efflux pumps. In this study, in-silico models are used to investigate the nature of the binding pocket of the MexAB-OprM efflux pump. First, we have performed Classical Molecular Dynamics (MD) simulations to shed light on different aspects of protein-inhibitor interaction in the binding pocket of the pump. Using classical molecular dynamics (MD) simulations, quantum mechanics/molecular mechanics QM/MM), and various types of analyses, we have shown that D13-9001 has a better binding affinity towards the binding pocket than D1 and D2 which was established experimentally. Two stable configurations of D13-9001 are discovered inside the distal pocket which could be one of the primary reason of the greater efficacy of D13-9001. Free energy barrier upon changing one state to another is calculated by employing umbrella sampling method. Finally, F178 is mutated to have the complete picture as it contributes a significant amount to the binding energy irrespective of the three inhibitors. The results of our study could be potentially used to design a new generation of inhibitors for such an efflux pump.