skip to main content
OSTI.GOV title logo U.S. Department of Energy
Office of Scientific and Technical Information

Title: Thermodynamic Coupling Function Analysis of Allosteric Mechanisms in the Human Dopamine Transporter

Abstract

Allostery plays a crucial role in the mechanism of neurotransmitter-sodium symporters, such as the human dopamine transporter. To investigate the molecular mechanism that couples the transport-associated inward release of the Na+ ion from the Na2 site to intracellular gating, we applied a combination of the thermodynamic coupling function (TCF) formalism and Markov state model analysis to a 50-μs data set of molecular dynamics trajectories of the human dopamine transporter, in which multiple spontaneous Na+ release events were observed. Our TCF approach reveals a complex landscape of thermodynamic coupling between Na+ release and inward-opening, and identifies diverse, yet well-defined roles for different Na+-coordinating residues. In particular, we identify a prominent role in the allosteric coupling for the Na+-coordinating residue D421, where mutation has previously been associated with neurological disorders. Our results highlight the power of the TCF analysis to elucidate the molecular mechanism of complex allosteric processes in large biomolecular systems.

Authors:
; ; ; ;
Publication Date:
Research Org.:
Oak Ridge National Lab. (ORNL), Oak Ridge, TN (United States). Oak Ridge Leadership Computing Facility (OLCF); UT-Battelle LLC/ORNL, Oak Ridge, TN (Unted States)
Sponsoring Org.:
USDOE Office of Science (SC)
OSTI Identifier:
1565645
DOE Contract Number:  
AC05-00OR22725
Resource Type:
Journal Article
Journal Name:
Biophysical Journal
Additional Journal Information:
Journal Volume: 114; Journal Issue: 1; Journal ID: ISSN 0006-3495
Publisher:
Elsevier
Country of Publication:
United States
Language:
English
Subject:
Biophysics

Citation Formats

LeVine, Michael V., Cuendet, Michel A., Razavi, Asghar M., Khelashvili, George, and Weinstein, Harel. Thermodynamic Coupling Function Analysis of Allosteric Mechanisms in the Human Dopamine Transporter. United States: N. p., 2018. Web. doi:10.1016/j.bpj.2017.10.030.
LeVine, Michael V., Cuendet, Michel A., Razavi, Asghar M., Khelashvili, George, & Weinstein, Harel. Thermodynamic Coupling Function Analysis of Allosteric Mechanisms in the Human Dopamine Transporter. United States. doi:10.1016/j.bpj.2017.10.030.
LeVine, Michael V., Cuendet, Michel A., Razavi, Asghar M., Khelashvili, George, and Weinstein, Harel. Mon . "Thermodynamic Coupling Function Analysis of Allosteric Mechanisms in the Human Dopamine Transporter". United States. doi:10.1016/j.bpj.2017.10.030.
@article{osti_1565645,
title = {Thermodynamic Coupling Function Analysis of Allosteric Mechanisms in the Human Dopamine Transporter},
author = {LeVine, Michael V. and Cuendet, Michel A. and Razavi, Asghar M. and Khelashvili, George and Weinstein, Harel},
abstractNote = {Allostery plays a crucial role in the mechanism of neurotransmitter-sodium symporters, such as the human dopamine transporter. To investigate the molecular mechanism that couples the transport-associated inward release of the Na+ ion from the Na2 site to intracellular gating, we applied a combination of the thermodynamic coupling function (TCF) formalism and Markov state model analysis to a 50-μs data set of molecular dynamics trajectories of the human dopamine transporter, in which multiple spontaneous Na+ release events were observed. Our TCF approach reveals a complex landscape of thermodynamic coupling between Na+ release and inward-opening, and identifies diverse, yet well-defined roles for different Na+-coordinating residues. In particular, we identify a prominent role in the allosteric coupling for the Na+-coordinating residue D421, where mutation has previously been associated with neurological disorders. Our results highlight the power of the TCF analysis to elucidate the molecular mechanism of complex allosteric processes in large biomolecular systems.},
doi = {10.1016/j.bpj.2017.10.030},
journal = {Biophysical Journal},
issn = {0006-3495},
number = 1,
volume = 114,
place = {United States},
year = {2018},
month = {1}
}