Molecular simulations of RNA 2′-O-transesterification reaction models in solution

Brian K. Radak, Michael E. Harris, Darrin York

Research output: Contribution to journalArticle

19 Citations (Scopus)

Abstract

We employ quantum mechanical/molecular mechanical umbrella sampling simulations to probe the free energy surfaces of a series of increasingly complex reaction models of RNA 2′-O-transesterification in aqueous solution under alkaline conditions. Such models are valuable for understanding the uncatalyzed processes underlying catalytic cleavage of the phosphodiester backbone of RNA, a reaction of fundamental importance in biology. The chemically reactive atoms are modeled by the AM1/d-PhoT quantum model for phosphoryl transfer, whereas the aqueous solvation environment is modeled with a molecular mechanics force field. Several simulation protocols were compared that used different ionic conditions and force field models. The results provide insight into how variation of the structural environment of the nucleophile and leaving group affects the free energy profile for the transesterification reaction. Results for a simple RNA backbone model are compared with recent experiments by Harris et al. on the specific base-catalyzed cleavage of a UpG dinucleotide. The calculated and measured free energies of activation match extremely well (ΔF⧠= 19.9-20.8 vs 19.9 kcal/mol). Solvation is seen to play a crucial role and is characterized by a network of hydrogen bonds that envelopes the pentacoordinate dianionic phosphorane transition state and provides preferential stabilization relative to the reactant state.

Original languageEnglish (US)
Pages (from-to)94-103
Number of pages10
JournalJournal of Physical Chemistry B
Volume117
Issue number1
DOIs
StatePublished - Jan 10 2013

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Transesterification
RNA
Free energy
free energy
Solvation
simulation
field theory (physics)
solvation
cleavage
Phosphoranes
Nucleophiles
Molecular mechanics
nucleophiles
biology
Hydrogen bonds
envelopes
Stabilization
stabilization
Chemical activation
sampling

All Science Journal Classification (ASJC) codes

  • Physical and Theoretical Chemistry
  • Surfaces, Coatings and Films
  • Materials Chemistry

Cite this

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abstract = "We employ quantum mechanical/molecular mechanical umbrella sampling simulations to probe the free energy surfaces of a series of increasingly complex reaction models of RNA 2′-O-transesterification in aqueous solution under alkaline conditions. Such models are valuable for understanding the uncatalyzed processes underlying catalytic cleavage of the phosphodiester backbone of RNA, a reaction of fundamental importance in biology. The chemically reactive atoms are modeled by the AM1/d-PhoT quantum model for phosphoryl transfer, whereas the aqueous solvation environment is modeled with a molecular mechanics force field. Several simulation protocols were compared that used different ionic conditions and force field models. The results provide insight into how variation of the structural environment of the nucleophile and leaving group affects the free energy profile for the transesterification reaction. Results for a simple RNA backbone model are compared with recent experiments by Harris et al. on the specific base-catalyzed cleavage of a UpG dinucleotide. The calculated and measured free energies of activation match extremely well (ΔF{\^a}§ = 19.9-20.8 vs 19.9 kcal/mol). Solvation is seen to play a crucial role and is characterized by a network of hydrogen bonds that envelopes the pentacoordinate dianionic phosphorane transition state and provides preferential stabilization relative to the reactant state.",
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Molecular simulations of RNA 2′-O-transesterification reaction models in solution. / Radak, Brian K.; Harris, Michael E.; York, Darrin.

In: Journal of Physical Chemistry B, Vol. 117, No. 1, 10.01.2013, p. 94-103.

Research output: Contribution to journalArticle

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