Reverse transcription in HIV-1 is a post entry event during which deoxy-nucleotide triphosphates (dNTPs) fuel cDNA synthesis. Importantly, it requires the availability of dNTPs inside the virus core. The central cavity located within capsid protein (CA) hexamers has been postulated as a dNTP channel and, thus, regulate dNTP import into complete cores. However, the molecular mechanism of the nucleotide translocation remains unclear. In addition, small molecules like inositol hexakisphosphate (IP<sub>6</sub>) and mellitic acid (MA) have been reported to bind to CA-hexamers and influence reverse transcription. But little is known about their roles in the nucleotide import. Here, we systematically designed and performed a series of all-atom molecular dynamics simulations to determine the molecular mechanisms associated with the trafficking of nucleotides through the central cavity of CA-hexamers. Results from our simulations demonstrate that a single nucleotide binds inside the cavity and that passive translocation of dNTPs is energetically unfavorable. However, a cooperative model where multiple nucleotides interact inside the cavity results in energetically favorable conditions for dNTP import. Our cooperative model was extended to IP<sub>6</sub> and MA, establishing that the former has an enhancing effect on dNTP import while the latter inhibits it. Altogether, our results reveal an atomistic mechanism for the HIV-1 dNTP-import and shed light on the development of new HIV-1 antiviral drugs.

Molecular mechanisms of nucleotide import through HIV-1 capsid hexamers

Macromolecular Chemistry: The Second Century

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ACS Spring 2020 National Meeting & Expo

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