title: Structural dynamics of the monoamine transporter homolog LeuT from accelerated conformational sampling and channel analysis.
abstract: The bacterial leucine transporter LeuT retains significant secondary structure similarities to the human monoamine transporters (MAT) such as the dopamine and serotonin reuptake proteins. The primary method of computational study of the MATs has been through the use of the crystallized LeuT structure. Different conformations of LeuT can give insight into mechanistic details of the MAT family. A conformational sampling performed through accelerated molecular dynamics simulations testing different combinations of the leucine substrate and bound sodium ions revealed seven distinct conformational clusters. Further analysis has been performed to target salt-bridge residues R30-D404, Y108-F253, and R5-D369 and transmembrane domains on both the seven isolated structures and the total trajectories. In addition, solvent accessibility of LeuT and its substrate binding pockets has been analyzed using a program for calculating channel radii. Occupation of the Na2 site stabilizes the outward conformation and should bind to the open outward conformation before the leucine and Na1 sodium while two possible pathways were found to be available for intracellular transport.
authors.affiliation: Department of Chemistry and Biochemistry and the Center for Computational Sciences, Duquesne University, Pittsburgh, Pennsylvania; Mylan School of Pharmacy, Duquesne University, Pittsburgh, Pennsylvania.
authors.forename: James R
authors.initials: JR
authors.lastname: Thomas
authors.forename: Patrick C
authors.initials: PC
authors.lastname: Gedeon
authors.forename: Jeffry D
authors.initials: JD
authors.lastname: Madura
mesh_terms: D006801:Humans; D007473:Ion Channels / Q000737:chemistry*; D017136:Ion Transport; D007930:Leucine / Q000737:chemistry*; D008958:Models, Molecular; D056004:Molecular Dynamics Simulation; D050480:Plasma Membrane Neurotransmitter Transport Proteins / Q000737:chemistry*; D025341:Principal Component Analysis; D011487:Protein Conformation
chemical_list: D007473:Ion Channels; D050480:Plasma Membrane Neurotransmitter Transport Proteins; D007930:Leucine
keywords: APC; FIRL; HOLE; molecular dynamics; monoamine transporter; principal component analysis
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