Multiscale Modeling of Wobble to Watson–Crick-Like Guanine–Uracil Tautomerization Pathways in RNA

Abstract

Energetically unfavorable Watson–Crick (WC)-like tautomeric forms of nucleobases are known to introduce spontaneous mutations, and contribute to replication, transcription, and translation errors. Recent NMR relaxation dispersion techniques were able to show that wobble (w) G•U mispair exists in equilibrium with the short-lived, low-population WC-like enolic tautomers. Presently, we have investigated the wG•U → WC-like enolic reaction pathway using various theoretical methods: quantum mechanics (QM), molecular dynamics (MD), and combined quantum mechanics/molecular mechanics (QM/MM). The previous studies on QM gas phase calculations were inconsistent with experimental data. We have also explored the environmental effects on the reaction energies by adding explicit water. While the QM-profile clearly becomes endoergic in the presence of water, the QM/MM-profile remains consistently endoergic in the presence and absence of water. Hence, by including microsolvation and QM/MM calculations, the experimental data can be explained. For the G•Uenol→ Genol•U pathway, the latter appears to be energetically more favorable throughout all computational models. This study can be considered as a benchmark of various computational models of wG•U to WC-like tautomerization pathways with and without the environmental effects, and may contribute on further studies of other mispairs as well.

Multiscale QM/MM modelling of catalytic systems with ChemShell

“…149 QM/MM simulations of biomolecules are not limited to proteins, and several recent ChemShell studies have focussed on DNA, RNA, and their components. [150][151][152][153][154][155][156][157] Biocatalysis applications involving DNA repair enzymes are an active topic in this area. [158][159][160][161] Naydenova et al used ChemShell to investigate the catalytic mechanism of uracil DNA glycosylase, which initiates excision of uracil DNA lesions.…”

Intramolecular proton transfer reaction dynamics using machine-learned ab initio potential energy surfaces

“…Hydrogen bonding interactions are essential in a variety of physicochemical processes, such as enzymatic catalysis [1][2][3][4][5], protein-protein interactions [6], nucleobase interactions in RNA and DNA [7], solid-liquid interfaces [8,9], polymerizations [10], and molecular recognition [11]. Hydrogen bonding interactions, which are considered as electrostatic in nature, can also have a certain amount of covalency in the bonding characteristics [12,13].…”

Quantum Tunnelling Effects in the Guanine-Thymine Wobble Misincorporation via Tautomerism

“…While there are other sources of replication errors, the fidelity of replication primarily depends on the ability of polymerases to select and incorporate the correct complementary base (see Figure ) and reject wobble mispairs. However, it is proposed − that a wobble mismatch can form alternative tautomeric configurations that can mimic the WC geometry and lead to erroneous DNA base matches, such as wobble­(G-T) → G*-T, where G* is the tautomeric (enol) form of the G base . Watson–Crick-like mispairs have been observed in the active sites of DNA polymerases ,, and ribosomes in enzymatically competent conformations. ,, Both nuclear magnetic resonance (NMR) relaxation dispersion experiments and simulations − indicate that the concentration of tautomeric mismatches in the cellular environment is significant and has a considerable impact on the replication fidelity of the polymerase.…”

“…As highlighted by previous computational studies, the role of proton transfer in spontaneous mutation is a complex affair. 5 , 8 , 17 However, the proton transfer mechanism in the polymerase is a prominent candidate as a source of mutations as it is later in the replication cycle and could play a role that is more significant than that played by other equilibria competing during mutation. Furthermore, for mechanisms involving double-stranded Watson–Crick DNA, it needs to be clarified if the helicase or another mechanism reduces the proton transfer populations via electrostatic destabilization or exonuclease proofreading mechanisms.…”