Human Immunodeficiency Virus Viral Infectivity Factor (HIV-Vif) is a protein that hijacks human cells’ ubiquitination process to promote the break down of antiviral proteins. The Vif protein does this by hijacking Cullin-RING E3 ligase (CRL), a complex naturally used to mark unwanted proteins in cells for degradation, and selectively targets and marks APOBEC3, an antiviral protein family. Vif is intrinsically disordered, and binds to a forming CRL to gain stability and functionality. Through molecular dynamics simulations, we are evaluating free energy per residue of this complex as it changes conformation to identify where mutations may impact the conformational ensemble. Principle component analysis was used to categorize types of global motion and conformational clusters. Differences in conformational clusters’ free energy per residue were compared to single out residues that may be involved in promoting one conformation over another. Three residues of the zinc binding domain were found to have the greatest difference in free energy between conformational clusters. Mutating residues that promote a conformation will likely alter the conformational ensemble of the complex, potentially impacting its function. Studying these mutations and their impacts can inform future research on pharmaceutical designs as well as inform researchers where HIV-Vif’s structure may evolve to interact with different forms of the ubiquitination complex. There have been changes in Vif’s sequence between HIV and SIVs to conform to different host species ubiquitination complexes; future studies will include looking into how changes between sequence of simian ubiquitination complex and human ubiquitination complex affect dynamics and conformation.

Free energy analysis of HIV-Vif hijacked ubiquitination complex for mutation design

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.