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Ground State Destabilization in Uracil DNA Glycosylase: Let Us Not Forget “Tautomeric Strain” in Substrates
journal contribution
posted on 2019-08-23, 20:14 authored by Ranjita Das, Erik A. Vázquez-Montelongo, G. Andrés Cisneros, Judy I. WuEnzymes like uracil DNA glycosylase
(UDG) can achieve ground state
destabilization, by polarizing substrates to mimic rare tautomers.
On the basis of computed nucleus independent chemical shifts, NICS(1)zz, and harmonic oscillator model of electron
delocalization (HOMED) analyses, of quantum mechanics (QM) and quantum
mechanics/molecular mechanics (QM/MM) models of the UDG active site,
uracil is strongly polarized when bound to UDG and resembles a tautomer
>12 kcal/mol higher in energy. Natural resonance theory (NRT) analyses
identified a dominant O2 imidate resonance form for residue bound
1-methyl-uracil. This “tautomeric strain” raises the
energy of uracil, making uracilate a better than expected leaving
group. Computed gas-phase SN2 reactions of free and hydrogen
bonded 1-methyl-uracil demonstrate the relationship between the degree
of polarization in uracil and the leaving group ability of uracilate.