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Unraveling the Critical Role Played by Ado762'OH in the Post-Transfer Editing by Archaeal Threonyl-tRNA Synthetase.
- Source :
-
Journal of Physical Chemistry B . 1/25/2018, Vol. 122 Issue 3, p1092-1101. 10p. - Publication Year :
- 2018
-
Abstract
- Archaeal threonyl-tRNA synthetase (ThrRS) possesses an editing active site wherein tRNAThr that has been misaminoacylated with serine (i.e., Ser-tRNAThr) is hydrolytically cleaved to serine and tRNAThr. It has been suggested that the free ribose sugar hydroxyl of Ado76 of the tRNAThr (Ado762'OH) is the mechanistic base, promoting hydrolysis by orienting a nucleophilic water near the scissile Ser-tRNAThr ester bond. We have performed a computational study, involving molecular dynamics (MD) and hybrid ONIOM quantum mechanics/molecular mechanics (QM/MM) methods, considering all possible editing mechanisms to gain an understanding of the role played by Ado762'OH group. More specifically, a range of concerted or stepwise mechanisms involving four-, six-, or eight-membered transition structures (total of seven mechanisms) were considered. In addition, these seven mechanisms were fully optimized using three different DFT functionals, namely, B3LYP, M06-2X, and M06-HF. The M06-HF functional gave the most feasible energy barriers followed by the M06-2X functional. The most favorable mechanism proceeds stepwise through two six-membered ring transition states in which the Ado762'OH group participates, overall, as a shuttle for the proton transfer from the nucleophilic H2O to the bridging oxygen (Ado763'O) of the substrate. More specifically, in the first step, which has a barrier of 25.9 kcal/mol, the Ado762'-OH group accepts a proton from the attacking nucleophilic water while concomitantly transferring its proton onto the substrates C-Ocarb center. Then, in the second step, which also proceeds with a barrier of 25.9 kcal/mol, the Ado762'-OH group transfers its proton on the adjacent Ado763'-oxygen, cleaving the scissile Ccarb-O3'Ado76 bond, while concomitantly accepting a proton from the previously formed C-OcarbH group. [ABSTRACT FROM AUTHOR]
- Subjects :
- *TRANSFER RNA
*QUANTUM mechanics
*NUCLEOPHILIC reactions
*BINDING sites
*PROTONS
Subjects
Details
- Language :
- English
- ISSN :
- 15206106
- Volume :
- 122
- Issue :
- 3
- Database :
- Academic Search Index
- Journal :
- Journal of Physical Chemistry B
- Publication Type :
- Academic Journal
- Accession number :
- 137301321
- Full Text :
- https://doi.org/10.1021/acs.jpcb.7b10254