title: Molecular dynamics simulations of Na+/Cl(-)-dependent neurotransmitter transporters in a membrane-aqueous system.
abstract: We have performed molecular dynamics simulations of a homology model of the human serotonin transporter (hSERT) in a membrane environment and in complex with either the natural substrate 5-HT or the selective serotonin reuptake inhibitor escitalopram. We have also included a transporter homologue, the Aquifex aeolicus leucine transporter (LeuT), in our study to evaluate the applicability of a simple and computationally attractive membrane system. Fluctuations in LeuT extracted from simulations are in good agreement with crystallographic B factors. Furthermore, key interactions identified in the X-ray structure of LeuT are maintained throughout the simulations indicating that our simple membrane system is suitable for studying the transmembrane protein hSERT in complex with 5-HT or escitalopram. For these transporter complexes, only relatively small fluctuations are observed in the ligand-binding cleft. Specific interactions responsible for ligand recognition, are identified in the hSERT-5HT and hSERT-escitalopram complexes. Our findings are in good agreement with predictions from mutagenesis studies.
authors: MEMPHYS-Center for Biomembrane Physics, Department of Chemistry, Technical University of Denmark, Building 206, 2800 Kgs. Lyngby, Denmark.
authors: Anne Marie
authors: AM
authors: Jørgensen
authors: Lena
authors: L
authors: Tagmose
authors: Anne Marie M
authors: AM
authors: Jørgensen
authors: Klaus P
authors: KP
authors: Bøgesø
authors: Günther H
authors: GH
authors: Peters
mesh_terms: D001426:Bacterial Proteins / Q000737:chemistry / Q000378:metabolism; D001665:Binding Sites; D015283:Citalopram / Q000737:chemistry; D003198:Computer Simulation; D006801:Humans; D007930:Leucine / Q000737:chemistry / Q000378:metabolism; D008958:Models, Molecular; D011485:Protein Binding; D025941:Protein Interaction Mapping; D012701:Serotonin / Q000737:chemistry; D050486:Serotonin Plasma Membrane Transport Proteins / Q000737:chemistry* / Q000378:metabolism; D017367:Selective Serotonin Reuptake Inhibitors / Q000737:chemistry; D012965:Sodium Chloride / Q000737:chemistry* / Q000378:metabolism; D012997:Solvents; D013816:Thermodynamics; D014867:Water / Q000737:chemistry*
chemical_list: D001426:Bacterial Proteins; D015283:Citalopram; D007930:Leucine; D012701:Serotonin; D050486:Serotonin Plasma Membrane Transport Proteins; D017367:Selective Serotonin Reuptake Inhibitors; D012965:Sodium Chloride; D012997:Solvents; D014867:Water