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Transition Mechanism of the Human Dopamine Transporter via Molecular Dynamics Simulations

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Molecular dynamics simulations reveal the dopamine transport pathway and confirm key intermediates for therapeutic insights.

This research aims to elucidate the transition mechanism of the human dopamine transporter (hDAT) during dopamine transport.
Utilized molecular dynamics simulations of recently resolved hDAT structures.
Constructed a Markov State Model to describe dopamine transport pathways and conformational transitions.
Identified three novel intermediate states associated with the transport mechanism.
Characterized three key macrostate intermediates: Macrostate 5 (extracellular gate closure), Macrostate 4 (ion-release bottleneck), Macrostate 1 (outward-facing reset).
Established a sequential transport mechanism involving Na+ and dopamine dynamics, culminating in dopamine release.
Provided insights into gating kinetics and identified new potential therapeutic targets.

Ibrahim et al. (2026) studied this question.

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