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.