title: Structural and dynamic changes adopted by EmrE, multidrug transporter protein--Studies by molecular dynamics simulation.
abstract: EmrE protein transports positively charged aromatic drugs (xenobiotics) in exchange for two protons and thus provides bacteria resistance to variety of drugs. In order to understand how this protein may recognize ligands, the monomer and asymmetric apo-form of the EmrE dimer embedded in a heterogeneous phospholipid (POPE+POPG) membrane were studied by molecular dynamics simulations. Dimer is regarded as a functional form of the transporter, but to understand molecular aspects of its mode of action, a monomer was also included in our work. We analyzed hydrogen bonds which include inter- and intra-molecular interactions. Analyzing the long-lasting H-bond interactions, we found that water access to the internal transmembrane segments is regulated by residues with aromatic or basic side chains and fluctuating transmembrane helices. Our finding supports that GLU14 in EmrE apo-form is ready to interact or bind with substrate molecule. The analysis of distance center of masses and water entrance area indicate the feasibility of the dimer to undergo induced fit in order to accommodate a ligand. The results indicate that a binding pattern can be formed in the EmrE in such a way that GLU14 binds to the positively charged fragment of a substrate molecule, and other aromatic residues (i.e., TRP63 and TYR40) located in vicinity may accommodate other non-polar parts of substrate molecule. The results of our simulation also allow us to support experimentally testable hypotheses concerning functional inward-outward conformational changes of the protein.
authors.affiliation: Department of Pharmaceutical Technology and Biochemistry, Faculty of Chemistry, Gdansk University of Technology, Narutowicza St 11/12, 80-233Gdansk,Poland. Electronic address: monikapadariya1@gmail.com.
authors.forename: Monikaben
authors.initials: M
authors.lastname: Padariya
authors.affiliation: Department of Pharmaceutical Technology and Biochemistry, Faculty of Chemistry, Gdansk University of Technology, Narutowicza St 11/12, 80-233Gdansk,Poland. Electronic address: umekalat@gmail.com.
authors.forename: Umesh
authors.initials: U
authors.lastname: Kalathiya
authors.affiliation: Department of Pharmaceutical Technology and Biochemistry, Faculty of Chemistry, Gdansk University of Technology, Narutowicza St 11/12, 80-233Gdansk,Poland. Electronic address: maciekb@hypnos.chem.pg.gda.pl.
authors.forename: Maciej
authors.initials: M
authors.lastname: Baginski
mesh_terms: D000595:Amino Acid Sequence; D017920:Antiporters / Q000737:chemistry* / Q000648:ultrastructure*; D001665:Binding Sites; D003198:Computer Simulation; D029968:Escherichia coli Proteins / Q000737:chemistry* / Q000648:ultrastructure*; D008051:Lipid Bilayers / Q000737:chemistry*; D008956:Models, Chemical; D056004:Molecular Dynamics Simulation; D008969:Molecular Sequence Data; D011485:Protein Binding; D011487:Protein Conformation
chemical_list: D017920:Antiporters; D029968:Escherichia coli Proteins; D008051:Lipid Bilayers; C075436:EmrE protein, E coli
keywords: EmrE; Heterogeneous lipid bilayer; Molecular dynamics; Multidrug transporter; Small multidrug resistance (SMR) transporter