title: The drug binding sites and transport mechanism of the RND pumps from Mycobacterium tuberculosis: Insights from molecular dynamics simulations.
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. The proposed ligand binding mechanism shows peristaltic movements in the channel leading to the drug efflux. This study would be helpful in understanding the molecular basis of drugs resistance in Mtb.
authors.affiliation: School of Life Sciences, Central University of Himachal Pradesh, Kangra, Himachal Pradesh, India.
authors.forename: Padmani
authors.initials: P
authors.lastname: Sandhu
authors.affiliation: School of Life Sciences, Central University of Himachal Pradesh, Kangra, Himachal Pradesh, India. Electronic address: yusuf@daad-alumni.de.
authors.forename: Yusuf
authors.initials: Y
authors.lastname: Akhter
mesh_terms: D001426:Bacterial Proteins / Q000737:chemistry* / Q000648:ultrastructure; D001665:Binding Sites; D004058:Diffusion; D026901:Membrane Transport Proteins / Q000737:chemistry* / Q000648:ultrastructure*; D008956:Models, Chemical; D056004:Molecular Dynamics Simulation; D009169:Mycobacterium tuberculosis / Q000737:chemistry*; D004364:Pharmaceutical Preparations / Q000737:chemistry*; D011485:Protein Binding; D011487:Protein Conformation; D025941:Protein Interaction Mapping
chemical_list: D001426:Bacterial Proteins; D026901:Membrane Transport Proteins; D004364:Pharmaceutical Preparations
keywords: Drug transport; Efflux pumps; MmpL5 protein; Multidrug resistance; Mycobacterium tuberculosis; RND transporters