We curated 91 MTases for analyses of enzyme interior electric field and cavity size of The curated MTases involves a diverse range of substrate specificity (Figure ) with nucleic acids and histones being the most abundant, representing 55.0% and 23.1% of the dataset, respectively. MTases catalyzing small molecules (i.e., molecular weight ≤582.9 g/mol), proteins and catechol each contribute 11.0%, 7.7% and 3.3% of the structures, respectively. We isolated catechol from the category of small molecules because of its high abundance and well-established existing studies elucidating its mechanism. Next, we investigated the electrostatic mediation of MTases on SAM co-factor with substrates containing different methyl-accepting polar atoms. We observe statistically significant differences in the distribution of electric field strengths for O-and N-targeting MTases (Figure , left). The EF strengths of O-targeting MTases are on average 136.0 MV/cm more negative than those targeting nitrogen. Using student's t-test, the electric field distributions are statistically significant with a p-value of 1.95x10 -6 . The average electric field of 20.0 MV/cm for N-targeting MTases is 62.1% more positive than the 13.8 MV/cm average field for the broader dataset. The results show that the protein scaffolds of N-targeting MTases have evolved more positive electric fields to overcome the lower electronegativity of nitrogen, in turn making it a better acceptor of SAM's methyl group. Oxygen's stronger electronegativity makes it a naturally stronger methyl group acceptor, and therefore, MTases take less efforts to evolve their interior electric field.