Journal
JOURNAL OF BIOLOGICAL INORGANIC CHEMISTRY
Volume 25, Issue 1, Pages 89-98Publisher
SPRINGER
DOI: 10.1007/s00775-019-01741-7
Keywords
RNase III; QM; MM; DFTB; Reaction mechanism; dsRNA
Funding
- CONICET
- Universidad Nacional de Rosario
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The ribonuclease III (RNase III) cleaves dsRNA in specific positions generating mature RNAs. RNase III enzymes play important roles in RNA processing, post-transcriptional gene expression, and defense against viral infection. The enzyme's active site contains Mg2+ ions bound by a network of acidic residues and water molecules, but there is a lack of information about their specific roles. In this work, multiple steered molecular dynamics simulations at QM/MM level were performed to explore the hydrolysis reaction carried out by the enzyme. Free energy profiles modifying the features of the active site are obtained and the role of Mg2+ ions, the solvent molecules and the residues of the active site are discussed in detail. Our results show that Mg2+ ions carry out different roles in the hydrolysis process positioning the substrate for the attack from a coordinated nucleophile and activating it to perform hydrolysis reaction, cleaving the dsRNA backbone in a S(N)2 substitution. In addition, water molecules present in the active site lower the energy barrier of the process. [GRAPHICS] .
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