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Multiscale Modeling of Watson-Crick-like Guanine-Uracil Mispair Tautomerization PathwaysAuthor: Shreya Chandorkar Date: 2021-07-16 Report no: IIIT/TH/2021/88 Advisor:Deva U Priyakumar AbstractEnergetically 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 performed structural and energetical characterizations of various intermediates and transition states along the reaction pathway. We have also explored the environmental effects on the reaction energies by adding explicit water. While QM-profile clearly becomes endoergic in the presence of water, QM/MM-profile remains consistently endoergic in the presence and absence of water. Hence, by including microsolvation and QM/MM calculations, experimental data can be explained. For G•U enol → G enol•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 to further studies of other mispairs as well. The first chapter gives the background on base mispairs. In chapter two, we give a brief introduction to the methods we have used - quantum mechanics, molecular dynamics and combined quantum mechanics/molecular mechanics. Chapter three deals with the results, analysis, and discussion. Finally, chapter four presents the conclusions of the study. Full thesis: pdf Centre for Computational Natural Sciences and Bioinformatics |
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