Chloroperoxidase (CPO) is a heme-thiolate protein with exceptional versatility and great potential as a biocatalyst. The CPO reactive species, Compound I ( Cpd I) is of particular interest, as well as the Cytochrome P450 (P450) -type monoxygenase catalytic activity, which has significant biotechnological potential. Proximal hydrogen bonding of the axial sulfur with the backbone amides (NH•••S) is a conserved feature of heme-thiolate enzymes. In CPO, the effect of NH•••S bonds is amplified by the dipole moment of the proximal helix. The role of the proximal region has been disputed as to whether it simply protects the axial sulfur, or whether it additionally influences catalysis via modulation of the push effect. The objective of the research presented herein is two-fold. First, the influence of the NH•••S bonds on Cpd I formation is determined by obtaining the reaction coordinate, starting from a peroxide bound heme, for two model systems (one with proximal residues providing NH•••S bonds and one without) and comparing the results. Secondly, the influence of the proximal region on the epoxidation of Cis-β-methylsterene is obtained. This is performed similarly to the first objective however, the reaction coordinate begins with a Cpd I-CBMS complex and the proximal contribution is extended to include the influence of the proximal helix dipole. Our findings show that the proximal region stabilizes Cpd 0 relative to all other minima and reduces the barrier for Cpd 0’s formation. The stability of protonated Compound 0 is reduced, favoring a hybrid homo-heterolytic relative to a classic heterolytic mechanism for O-O bond scission. Additionally, the proximal region significantly enhances CPO’s reactivity; the Cβ-O bond barrier is stabilized, while Cα-O-Cβ ring closure becomes barrierless. The stabilization of the reaction barrier correlates with increased electron density transfer to residues of the proximal pocket and involves a change in the electron transfer mechanism. These results can be traced to a reduction in the pKa of the heme-bound substrate and an increase in oxidation potential, a result of the proximal region reducing the “push effect”.