The drug binding sites and transport mechanism of the RND pumps from Mycobacterium tuberculosis: Insights from molecular dynamics simulations

Archives of Biochemistry and Biophysics
Padmani Sandhu, Yusuf Akhter

Abstract

RND permease superfamily drug efflux pumps are involved in multidrug transport and are attractive to study them for therapeutic purpose. In previous work we have classified 14 members of MmpL proteins belong to RND superfamily from Mycobacterium tuberculosis (Mtb) within its families [Sandhu P. and Akhter Y., 2015. Int. J. Med. Microbiol., 305:413-423]. In this study, structures of these proteins are homology modelled. The drug binding sites and channels are identified using local micro-stereochemistry and charge densities. Potential transport mechanism based on differential structural behaviour in the absence and on the binding of drug molecules is explained using the molecular dynamics simulation results. Our studies show two potential drug binding sites positioned at opposite ends of the transport tunnel leading from cytoplasmic to the periplasmic space across MmpL5 trimer. The drug binding have effects on the structural conformation of the protein leading to molecular-scale peristaltic movements. The free binding energy calculations reveal that the subsequent binding events are interdependent and may have implications on transport mechanism. Two drug binding sites and a continuous channel in the RND pump have been reported....Continue Reading

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Citations

Aug 9, 2016·The International Journal of Biochemistry & Cell Biology·Indu KumariYusuf Akhter
Nov 7, 2016·International Journal of Biological Macromolecules·Nitika ChaudharyYusuf Akhter
Mar 25, 2017·Molecular Microbiology·Albertus ViljoenLaurent Kremer
Feb 24, 2017·Journal of Inorganic Biochemistry·Padmani Sandhu, Yusuf Akhter
Sep 28, 2017·Archives of Microbiology·Padmani Sandhu, Yusuf Akhter
Jan 9, 2019·Frontiers in Microbiology·Diana MachadoMiguel Viveiros
Oct 12, 2017·Journal of Biological Inorganic Chemistry : JBIC : a Publication of the Society of Biological Inorganic Chemistry·Razak HussainYusuf Akhter
Feb 9, 2020·Molecules : a Journal of Synthetic Chemistry and Natural Product Chemistry·Stephani Joy Y MacalinoMaria Constancia O Carrillo
Jul 22, 2021·Computational and Structural Biotechnology Journal·Alexander D H Kingdon, Luke J Alderwick
Oct 16, 2016·ACS Infectious Diseases·Juan Manuel BelardinelliMary Jackson

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