Molecular dynamics simulations of Na+/Cl(-)-dependent neurotransmitter transporters in a membrane-aqueous system

ChemMedChem. 2007 Jun;2(6):827-40. doi: 10.1002/cmdc.200600243.


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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Bacterial Proteins / chemistry
  • Bacterial Proteins / metabolism
  • Binding Sites
  • Citalopram / chemistry
  • Computer Simulation*
  • Humans
  • Leucine / chemistry
  • Leucine / metabolism
  • Models, Molecular*
  • Protein Binding
  • Protein Interaction Mapping
  • Serotonin / chemistry
  • Serotonin Plasma Membrane Transport Proteins / chemistry*
  • Serotonin Plasma Membrane Transport Proteins / metabolism
  • Serotonin Uptake Inhibitors / chemistry
  • Sodium Chloride / chemistry*
  • Sodium Chloride / metabolism
  • Solvents
  • Thermodynamics*
  • Water / chemistry*


  • Bacterial Proteins
  • Serotonin Plasma Membrane Transport Proteins
  • Serotonin Uptake Inhibitors
  • Solvents
  • Water
  • Citalopram
  • Serotonin
  • Sodium Chloride
  • Leucine