Abstract
Metalloenzymes play essential roles in biology. However, unraveling how outer-sphere interactions can be predictably controlled to influence their functions remains a significant challenge. Inspired by Cu enzymes, we demonstrate how variations in the primary, secondary, and outer coordination-sphere interactions of de novo designed artificial copper proteins (ArCuPs) within trimeric (3SCC) and tetrameric (4SCC) self-assemblies-featuring a trigonal Cu(His)(3) and a square pyramidal Cu(His)(4)(OH(2)) coordination-influence their catalytic and electron transfer properties. While 3SCC electrocatalyzes C-H oxidation, 4SCC does not. Cu(I)-3SCC reacts more rapidly with H(2)O(2) than O(2), whereas 4SCC is less active. Electron transfer, reorganization energies, and extended H(2)O-mediated hydrogen bonding patterns provide insights into the observed reactivity differences. The inactivity of 4SCC is attributed to a significant solvent reorganization energy barrier mediated by a specific His---Glu hydrogen bond. When this hydrogen bond is disrupted, the solvent reorganization energy is reduced, and C-H peroxidation activity is restored.