Molecular Modeling Study On The Recognition Mechanism Between Adenosine Deaminases That Act On RNA And Nucleic Acids

Researches on the ADARs (Adenosine Deaminases that Act on RNA) are hot since the first discovery on the A-to-I (Adenosine to Inosine) RNA editing activity of ADARs. Regulation of A-to-I editing could change the RNA structure and coding, result in protein diversity and make important effects on the relative biological process. Both ADAR1and ADAR2are families of ADARs with RNA editing activities and different structure characteristics. ADAR1has two Z-DNA binding domains (Zα and Zβ) that are unique structure characteristic for ADAR1compared to other ADARs members, while ADAR2can sequence specifically recognize the dsRNA and may exist as a dimer. For now there are only a few experimental researches on the interaction between ADARs and DNA/RNA. In this paper, we used molecular dynamics simulation (MD simulation) to study comprehensively about the ADARs systems. The results are important to further explore the ADARs’ vital processes and functions, and at the same time provide references and foundation for studying other similar interactions. MD simulation approach can provide dynamic information of the interaction between ADARs and its binding nucleic acids at atomic level, which is difficult to obtain or can not be predicted from the experiments. Our present work focused on the recognition mechanisms between two ADARs and nucleic acids. First, we studied the recognition mechanism of human ADAR1Z-DNA binding domain Za (hZαADAR1) and Z-DNA by comparing the binding details between Z-DNA with different sequences and hZaADAR1·Our results were consistent with experiments and explained the mechanism from dynamic levels—hZαADARi contacts with Z-DNA may depend on the Z-DNA conformation but not the sequence. Second, we studied the specific recognition between human ADAR2dsRBM and dsRNA, and further discussed the effects of mutations on ADAR2editing activity by mutating amino acids of dsRBM. The results showed that dsRBMs bind with dsRNA through two specific domains and the mutations of specific binding residues could change dsRBMs’conformations which indirectly reduce ADAR2editing activity. Our results provide references for the further understanding of interactions between similar proteins and nucleic acids.