Protein-Enforced Ligand Environments Reshape Classical Coordination Preferences in Copper Polypyridyl Complexes.

Copper coordination chemistry is governed by several well-established features, including Jahn-Teller distortion in octahedral Cu(II) complexes and the scarcity of high-coordinate Cu(I) species. Here, we demonstrate that protein scaffolds can function as mechanically active ligand architectures that override these intrinsic electronic and structural preferences. We designed four protein scaffolds that preorganize two or three bipyridine-alanine noncanonical amino acids to generate mononuclear copper sites in either the cupric or cuprous state. These protein-embedded complexes exhibit distinct charge-transfer features, enhanced structural symmetry with significantly reduced Jahn-Teller distortion, an unprecedented octahedral Cu(I) geometry, markedly cathodic shifts in Cu(II)/Cu(I) redox potentials, and rapid self-exchange rate constants consistent with entatic-state behavior. Collectively, this work establishes protein-based multidentate ligands as a general strategy to access nonclassical coordination environments and to expand the chemical space and reactivity of metalloproteins through protein-imposed strains.