Ground State Destabilization in Uracil DNA Glycosylase: Let's Not Forget "Tautomeric Strain" in Substrates.

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-methyl-uracil. This "tautomeric strain" raises the energy of uracil, making uracilate a better than expected leaving group. Computed gas-phase S_N2 reactions of free and hy

SUBMITTER: Das R 

PROVIDER: S-EPMC6726543 | biostudies-literature | 2019 Sep

REPOSITORIES: biostudies-literature