<br/>HIV and HTLV are human retroviruses that are directly responsible for the death of over 32 million people globally. Both viruses share a common drug target known as retroviral protease (PR). Retroviral proteases are dimeric, where each monomer contributes a beta-hairpin flap that acts as a gate to the active site. Using Molecular Dynamics compared to Electron Paramagnetic Resonance, we previously showed that the flaps open to allow the substrate/inhibitor entrance into the active site, and close upon substrate binding. It has been hypothesized that this opening mechanism can be targeted using an allosteric inhibition strategy. Research has shown that retroviral proteases have similar functionality but different substrate specificity. Therefore our goal is to characterize the opening mechanism in MDR sequences of HIV-1 Pr, HTLV-1 PR and the proteases of the first discovered retrovirus (RSV PR) and identify any commonality in their dynamics. We performed a combined total of ~0.5 milliseconds of MD simulations on multiple sequences of HIV-1 PR, RSV-PR, and HTLV-1 PR. We used a 2D reaction coordinate that maps the conformational transitions to create free energy landscapes. The free energy landscapes were used to elucidate the similarities and differences in the opening mechanism across retroviral proteases.

Elucidating the opening mechanism in retroviral proteases

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

The official archive and repository for all ACS Meetings & Expositions abstracts and select posters or presentations.