LeuT conformational sampling utilizing accelerated molecular dynamics and principal component analysis

Biophys J. 2012 Jul 3;103(1):L1-3. doi: 10.1016/j.bpj.2012.05.002.


Monoamine transporters (MATs) function by coupling ion gradients to the transport of dopamine, norepinephrine, or serotonin. Despite their importance in regulating neurotransmission, the exact conformational mechanism by which MATs function remains elusive. To this end, we have performed seven 250 ns accelerated molecular dynamics simulations of the leucine transporter, a model for neurotransmitter MATs. By varying the presence of binding-pocket leucine substrate and sodium ions, we have sampled plausible conformational states representative of the substrate transport cycle. The resulting trajectories were analyzed using principal component analysis of transmembrane helices 1b and 6a. This analysis revealed seven unique structures: two of the obtained conformations are similar to the currently published crystallographic structures, one conformation is similar to a proposed open inward structure, and four conformations represent novel structures of potential importance to the transport cycle. Further analysis reveals that the presence of binding-pocket sodium ions is necessary to stabilize the locked-occluded and open-inward conformations.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

  • Amino Acid Sequence
  • Animals
  • Humans
  • Leucine / chemistry
  • Molecular Dynamics Simulation
  • Molecular Sequence Data
  • Plasma Membrane Neurotransmitter Transport Proteins / chemistry*
  • Principal Component Analysis
  • Protein Conformation
  • Sodium / chemistry


  • Plasma Membrane Neurotransmitter Transport Proteins
  • Sodium
  • Leucine