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Configuration Flipping in Distal Pocket of Multidrug Transporter MexB Impacts the Efflux Inhibitory Mechanism
Author(s) -
Kumar Roy Rakesh,
Patra Niladri
Publication year - 2020
Publication title -
chemphyschem
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.016
H-Index - 140
eISSN - 1439-7641
pISSN - 1439-4235
DOI - 10.1002/cphc.202000759
Subject(s) - efflux , molecular dynamics , chemistry , pseudomonas aeruginosa , biophysics , transporter , umbrella sampling , molecular mechanics , atp binding cassette transporter , in silico , qm/mm , biochemistry , computational chemistry , biology , bacteria , genetics , gene
MexAB‐OprM efflux pumps, found in Pseudomonas aeruginosa , play 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 MD simulations, quantum mechanics/molecular mechanics (QM/MM), and various types of analyses, it is found that D13‐9001 has a higher binding affinity towards the binding pocket compared to D1 and D2; the results are in sync with the experimental dat. Two stable configurations of D13‐9001 are discovered inside the distal pocket which could be one of the primary reasons for the greater efficacy of D13‐9001. The 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 significantly to the binding energy irrespective of the three inhibitors. Our results may help to design a new generation of inhibitors for such an efflux pump.