Evaluating the Transition State Stabilization/Destabilization Effects of the Electric Fields from Scaffold Residues by a QM/MM Approach

The protein scaffolds of enzymes not only provide structural support for the catalytic center but also exert preorganized electric fields for electrostatic catalysis. In recent years, uniform oriented external electric fields (OEEFs) have been widely applied to enzymatic reactions to mimic the electrostatic effects of the environment. However, the electric fields exerted by individual residues in proteins may be quite heterogeneous across the active site, with varying directions and strengths at different positions of the active site. Here, we propose a QM/MM-based approach to evaluate the effects of the electric fields exerted by individual residues in the protein scaffold. In particular, the heterogeneity of the residue electric fields and the effect of the native protein environment can be properly accounted for by this QM/MM approach. A case study of the O-O heterolysis reaction in the catalytic cycle of TyrH shows that (1) for scaffold residues that are relatively far from the active site, the heterogeneity of the residue electric field in the active site is not very significant and the electrostatic stabilization/destabilization due to each residue can be well approximated with the interaction energy between a uniform electric field and the QM region dipole; (2) for scaffold residues near the active site, the residue electric fields can be highly heterogeneous along the breaking O-O bond. In such a case, approximating the residue electric fields as uniform fields may misrepresent the overall electrostatic effect of the residue. The present QM/MM approach can be applied to evaluate the residues' electrostatic impact on enzymatic reactions, which also can be useful in computational optimization of electric fields to boost the enzyme catalysis.