Cu-dependent enzymes constitute a significant class, facilitating bioenergy and healthcare-relevant chemical processes. Some examples include O2/H2O2 activation, lignocellulosic biomass degradation, hormone production, and methane oxidation. Although the factors beyond the primary coordination sphere significantly influence their reactivity, controlling outer-sphere interactions to influence functions predictably remains challenging. One approach to alleviate this issue is to design artificial metalloenzymes (ArMs), which still contain the metal of interest in a biomolecular environment. I will describe our recent efforts to control outer-sphere hydrogen bonding interactions via protein engineering and demonstrate how these interactions influence solvent reorganization barriers. A high solvent barrier abolishes the catalytic C-H peroxidation of one such ArM. However, the catalytic activity is restored when the solvent barrier is lowered by deleting outer-sphere hydrogen bonding interactions.