Molecular dynamics simulations of Ago silencing complexes reveal a large repertoire of admissible 'seed-less' targets.
Publication/Presentation Date
1-1-2012
Abstract
To better understand the recognition mechanism of RISC and the repertoire of guide-target interactions we introduced G:U wobbles and mismatches at various positions of the microRNA (miRNA) 'seed' region and performed all-atom molecular dynamics simulations of the resulting Ago-miRNA:mRNA ternary complexes. Our simulations reveal that many modifications, including combinations of multiple G:U wobbles and mismatches in the seed region, are admissible and result in only minor structural fluctuations that do not affect overall complex stability. These results are further supported by analyses of HITS-CLIP data. Lastly, introduction of disruptive mutations revealed a bending motion of the PAZ domain along the L1/L2 'hinge' and a subsequent opening of the nucleic-acid-binding channel. Our findings suggest that the spectrum of a miRNA's admissible targets is different from what is currently anticipated by the canonical seed-model. Moreover, they provide a likely explanation for the previously reported sequence-dependent regulation of unintended targeting by siRNAs.
Volume
2
First Page
569
Last Page
569
ISSN
2045-2322
Published In/Presented At
Xia, Z., Clark, P., Huynh, T., Loher, P., Zhao, Y., Chen, H. W., Ren, P., Rigoutsos, I., & Zhou, R. (2012). Molecular dynamics simulations of Ago silencing complexes reveal a large repertoire of admissible 'seed-less' targets. Scientific reports, 2, 569. https://doi.org/10.1038/srep00569
Disciplines
Business Administration, Management, and Operations | Health and Medical Administration | Management Sciences and Quantitative Methods
PubMedID
22888400
Department(s)
Administration and Leadership
Document Type
Article