Contributions of 3′-overhang to the dissociation of small interfering RNAs from the PAZ domain: Molecular dynamics simulation study

RNA interference (RNAi) is a ‘knock-down’ reaction to reduce expression of a specific gene through highly regulated, enzyme-mediated processes. Small interfering RNAs (siRNAs) are RNA molecules that play an effector role in RNAi and can bind the PAZ domains present in Dicer and RISC. We investigated the interaction between the PAZ domain and the siRNA-like duplexes through dissociation molecular dynamics (DMD) simulations. Specifically, we focused on the response of the PAZ domain to various 3′-overhang structures of the siRNA-like duplexes. We found that the siRNA-like duplex with the 3′ UU-overhang made relatively more stable complex with the PAZ domain compared to those with 3′ CC-, AA-, and GG-overhangs. The siRNA-like duplex with UU-overhang was easily dissociated from the PAZ domain once the structural stability of the complex is impaired. Interestingly, the 3′ UU-overhang spent the least time at the periphery region of the binding pocket during the dissociation process, which can be mainly attributable to UU-overhang's smallest number of hydrogen bonds.