Mycobacterium tuberculosis is known for a high concentration of mycolic acids which are essential for survival to damage, resistance to external factors such as antibiotics, and cell wall synthesis. The MmpL3 transporter protein is responsible for pumping out the precursor to mycolic acid, trehalose monomycolate (TDM), which occurs through the proton motive force, in which a proton is pumped in through the receptor to the cytoplasmic space and TMM and is transported out into the periplasmic space. Recently, crystal structures of the Mycobacterium smegmatis MmpL3 transporter protein and bound to a selection of MmpL3 inhibitors were made available by Zhang el al. 2019. One inhibitor crystalized with the protein SQ109, is currently under Phase II clinical trials and has shown promising results. Yet, its inhibition mechanism remains to be elusive. In this study, molecular dynamics (MD) simulations of both holo and apo-form of MmpL3 was used to decipher the inhibition mechanism of SQ109. We observed that while water molecules passed through the central channel of the transporter to the cytoplasmic side in the Apo system with the mean passing time of ~135 ns, this was observed in the holo system. Because water, as a proton carrier/shuttle, plays an important role in transporting proton. Our finding shed in light on the proton transportation in the apo form and the proton transportation inhibition by the inhibitor. In addition, key residues involving in water pass have a good overlap with the conserved resides within the protein family.

Probe the inhibition mechanism of SQ109, an investigative inhibitor of the Mycobacterium tuberculosis MmpL3 transporter protein using molecular dynamics simulations

ACS Fall 2021

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