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Abstract
Enzymes 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-methyluracil. This “tautomeric strain” raises the energy of uracil, making
uracilate a better than expected leaving group. Computed gas-phase S N 2 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.