Quantitative Assessment of the Energetics of Dopamine Translocation by Human Dopamine Transporter

J Phys Chem B. 2018 May 31;122(21):5336-5346. doi: 10.1021/acs.jpcb.7b10340. Epub 2017 Dec 26.


Computational evaluation of the energetics of substrate binding, transport, and release events of neurotransmitter transporters at the molecular level is a challenge, as the structural transitions of these membrane proteins involve coupled global and local changes that span time scales of several orders of magnitude, from nanoseconds to seconds. Here, we provide a quantitative assessment of the energetics of dopamine (DA) translocation through the human DA transporter (hDAT), using a combination of molecular modeling, simulation, and analysis tools. DA-binding and -unbinding events, which generally involve local configurational changes, are evaluated using free-energy perturbation or adaptive biasing force methods. The global transitions between the outward-facing state and the inward-facing state, on the other hand, require a dual-boost accelerated molecular dynamics simulation. We present results on DA-binding/unbinding energetics under different conditions, as well as the conformational energy landscape of hDAT in both DA-bound and -unbound states. The study provides a tractable method of approach for quantitative evaluation of substrate-binding energetics and efficient estimation of conformational energy landscape, in general.

Publication types

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

MeSH terms

  • Dopamine / chemistry
  • Dopamine / metabolism*
  • Dopamine Plasma Membrane Transport Proteins / chemistry
  • Dopamine Plasma Membrane Transport Proteins / metabolism*
  • Humans
  • Lipid Bilayers / chemistry
  • Lipid Bilayers / metabolism
  • Molecular Dynamics Simulation
  • Protein Binding
  • Protein Structure, Tertiary
  • Substrate Specificity
  • Thermodynamics


  • Dopamine Plasma Membrane Transport Proteins
  • Lipid Bilayers
  • Dopamine