A Markov State-based Quantitative Kinetic Model of Sodium Release from the Dopamine Transporter

Razavi, Asghar M.; Khelashvili, George; Weinstein, Harel

doi:10.1038/srep40076

Title: A Markov State-based Quantitative Kinetic Model of Sodium Release from the Dopamine Transporter

Journal Article · Fri Jan 06 00:00:00 EST 2017 · Scientific Reports

DOI:https://doi.org/10.1038/srep40076· OSTI ID:1490988

Razavi, Asghar M. ^[1]; Khelashvili, George ^[1]; Weinstein, Harel ^[2]

Cornell Univ., New York, NY (United States). Weill Cornell Medical College, Dept. of Physiology and Biophysics
Cornell Univ., New York, NY (United States). Weill Cornell Medical College, Dept. of Physiology and Biophysics and Inst. for Computational Biomedicine

Here, the dopamine transporter (DAT) belongs to the neurotransmitter:sodium symporter (NSS) family of membrane proteins that are responsible for reuptake of neurotransmitters from the synaptic cleft to terminate a neuronal signal and enable subsequent neurotransmitter release from the presynaptic neuron. The release of one sodium ion from the crystallographically determined sodium binding site Na2 had been identified as an initial step in the transport cycle which prepares the transporter for substrate translocation by stabilizing an inward-open conformation. We have constructed Markov State Models (MSMs) from extensive molecular dynamics simulations of human DAT (hDAT) to explore the mechanism of this sodium release. Our results quantify the release process triggered by hydration of the Na2 site that occurs concomitantly with a conformational transition from an outward-facing to an inward-facing state of the transporter. The kinetics of the release process are computed from the MSM, and transition path theory is used to identify the most probable sodium release pathways. An intermediate state is discovered on the sodium release pathway, and the results reveal the importance of various modes of interaction of the N-terminus of hDAT in controlling the pathways of release.

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Research Organization:: Oak Ridge National Laboratory (ORNL), Oak Ridge, TN (United States). Oak Ridge Leadership Computing Facility (OLCF); Lawrence Berkeley National Laboratory (LBNL), Berkeley, CA (United States). National Energy Research Scientific Computing Center (NERSC)

Sponsoring Organization:: USDOE Office of Science (SC)

Grant/Contract Number:: AC05-00OR22725; AC02-05CH11231

OSTI ID:: 1490988

Journal Information:: Scientific Reports, Vol. 7, Issue 1; ISSN 2045-2322

Publisher:: Nature Publishing GroupCopyright Statement

Country of Publication:: United States

Language:: English

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Cited by: 50 works

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Title: A Markov State-based Quantitative Kinetic Model of Sodium Release from the Dopamine Transporter

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