APOBEC3H (A3H) is a cytidine deaminase most well known for its involvement in innate human immunity to HIV. It exists primarily in an RNA-mediated dimer and acts preferentially upon a single-stranded DNA substrate containing a TCA consensus sequence. The Cisneros group recently reported a lung-cancer associated single nucleotide polymorphism on A3H that results in the A3H K121E missense variant (DNA Rep.,70, 2018, 10). Here, we characterize several aspects of A3H including substrate binding orientation and selectivity, RNA mediated interface features, and the impact on the structure/function of the cancer mutation. Our results are based on extensive molecular dynamics (MD) calculations totaling 11.25 μs of simulation time using the pmemd.cuda engine in the AMBER software suite and OpenMM on a combination of Nvidia K80 and V100 GPUs. Our calculations comprise eighteen monomer A3H systems (34,000 atoms) to investigate substrate binding and selectivity and four A3H dimer systems (260,000 atoms) to determine the impact of the cancer mutation. Based on our simulations, we have obtained a possible preferred substrate orientation, uncover residues responsible for the preferred A3H consensus sequence, and observed that the A3H K121E exhibits diminished stability at the dimer interface compared to the wild type A3H. More importantly, our simulations allowed us to predict a rescue mutation, K117E, to compensate the effects of the K121E cancer variant. These predictions have been tested and confirmed experimentally. The single point mutation K117E was also experimentally observed to produce a stable A3H, and was then tested computationally. In this poster I will present and discuss our computational predictions and experimental results.

Characterization of APOBEC3H substrate binding orientation/selectivity and effect of a lung–cancer associated mutation and rescue mutation

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.