The increase of HIV infection in macrophages results in HIV proteins being released, like HIV Tat which impairs the function of monoamine transporters. HIV-infected patients have displayed increased synaptic levels of dopamine (DA) due to reduced binding and function of monoamine transporters such as the norepinephrine transporter (NET) and the dopamine transporter (DAT). Development of a three-dimensional model of the HIV-1 Tat-human NET (hNET) binding complex would help reveal how HIV-1 Tat causes toxicity in the neuron by affecting DA uptake. Here we use computational techniques such as molecular modeling to study microscopic properties and molecular dynamics of the HIV-1 Tat-hNET binding. These modeling techniques allow us to analyze noncovalent interactions and observe residue-residue contacts to verify a model structure. The modeling results studied here show that HIV-1 Tat-hNET binding is highly dynamic and that HIV-1 Tat preferentially binds to hNET in its outward-open state. In particular, HIV-1 Tat forms hydrogen bond interactions with side chains of hNET residues Y84, K88, and T544. The favorable hydrogen bonding interactions of HIV-1 Tat with the hNET side chain residues Y84 and T544 have been validated by our subsequently performed DA uptake activity assays and site-directed mutagenesis, suggesting that the modeled HIV-1 Tat-hNET binding mode is reasonable. These mechanistic and structural insights gained through homology models discussed in this study are expected to encourage the pursuit of pharmacological and biochemical studies on HIV-1 Tat interacting with hNET mechanisms and detailed structures.
|Number of pages||9|
|Journal||ACS Chemical Neuroscience|
|State||Published - May 5 2021|
Bibliographical noteFunding Information:
This work was supported in part by the National Institutes of Health (R01 DA035714, P20 GM130456, and UL1 TR001998) and the National Science Foundation (NSF grant CHE-1111761). The authors also thank the University of Kentucky Computer Center for providing supercomputing time on a Dell Supercomputer Cluster consisting of 388 nodes or 4816 processors.
- Molecular docking
- molecular dynamics
- norepinephrine transporter
- protein-protein interaction
- trans-activator of transcription
ASJC Scopus subject areas
- Cognitive Neuroscience
- Cell Biology