In silico molecular docking analysis of the human Argonaute 2 PAZ domain reveals insights into RNA interference

• Published in: Journal of computer-aided molecular design 2013-07, Vol.27 (7), p.605-614
• Main Authors: Kandeel, Mahmoud, Kitade, Yukio
• Format: Article
• Language: English
• Subjects: Animal Anatomy; Argon; Argonaute Proteins - chemistry; Argonaute Proteins - metabolism; Binding energy; Binding Sites; Chemistry; Chemistry and Materials Science; Computer Applications in Chemistry; Computer based modeling; Computer Simulation; Drosophila; Gene expression; Gene Silencing; Histology; Human; Humans; Interference; Mathematical models; Molecular Docking Simulation; Molecular structure; Morphology; Physical Chemistry; Protein Conformation; Protein Structure, Tertiary; Proteins; Ribonucleic acid; Ribonucleic acids; RNA; RNA, Small Interfering - chemistry; Topology
• ISSN: 0920-654X; 1573-4951
• DOI: 10.1007/s10822-013-9665-3

RNA interference (RNAi) is a critical cellular pathway activated by double stranded RNA and regulates the gene expression of target mRNA. During RNAi, the 3′ end of siRNA binds with the PAZ domain, followed by release and rebinding in a cyclic manner, which deemed essential for proper gene silencing. Recently, we provided the forces underlying the recognition of small interfering RNA by PAZ in a computational study based on the structure of Drosophila Argonaute 2 (Ago2) PAZ domain. We have now reanalyzed these data within the view of the new available structures from human Argonauts. While the parameters of weak binding are correlated with higher (RNAi) in the Drosophila model, a different profile is predicted with the human Ago2 PAZ domain. On the basis of the human Ago2 PAZ models, the indicators of stronger binding as the total binding energy and the free energy were associated with better RNAi efficacy. This discrepancy might be attributable to differences in the binding site topology and the difference in the conformation of the bound nucleotides.