Computational modeling of human dopamine transporter structures, mechanism and its interaction with HIV-1 transactivator of transcription.

This is a brief review of computational modeling studies on the detailed structures and mechanism of human dopamine transporter (hDAT), as well as its interaction with HIV-1 transactivator of transcription (Tat). Extensive molecular modeling, docking and dynamics simulations have resulted in reasonable structural models of hDAT in three typical conformational states, its dopamine uptake mechanism and its interaction with Tat. The obtained hDAT models in different conformational states and their complexes with dopamine and Tat have provided novel structural and mechanistic insights concerning how hDAT uptakes dopamine and how Tat affects the dopamine uptake by hDAT. The computational insights, that are consistent with available experimental data, should be valuable for future rational design of novel therapeutic strategies for treatment of HIV-associated neurocognitive disorders.