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Molecular Dynamics Simulations of Na + /Cl − ‐Dependent Neurotransmitter Transporters in a Membrane‐Aqueous System
Author(s) -
Jørgensen Anne Marie,
Tagmose Lena,
Jørgensen Anne Marie M.,
Bøgesø Klaus P.,
Peters Günther H.
Publication year - 2007
Publication title -
chemmedchem
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.817
H-Index - 100
eISSN - 1860-7187
pISSN - 1860-7179
DOI - 10.1002/cmdc.200600243
Subject(s) - aquifex aeolicus , transporter , serotonin transporter , molecular dynamics , homology modeling , transmembrane domain , escitalopram , chemistry , reuptake , biophysics , amino acid transporter , serotonin plasma membrane transport proteins , transmembrane protein , neurotransmitter transporter , membrane , biochemistry , serotonin , biology , receptor , computational chemistry , antidepressant , neuroscience , escherichia coli , hippocampus , gene , enzyme
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.