Abstract
Herein, the σ-/π-hole chemistry of Co within a biological framework was computationally studied for the first time using Cobalamin (Cbl) as a case study. Starting with a Protein Data Bank (PDB) survey, 111 structures involving Cbl were found, 67 of which presented a noncovalent interaction (NCI) involving the Co atom and either substrate/product molecules, protein residues, or artificial ligands. These data were statistically analyzed to unveil trends regarding the abundance and structural features of the L···Co interaction (L = C, N, and O), and several selected examples were investigated at the BP86-D3/def2-TZVP level of theory. In addition, a computational study revealed the existence of a σ-hole complex involving the 5,6-dimethylbenzimidazole (DMB) group as a stabilizing prestate prior to Co coordination. This finding was further assessed by the identification of several local noncovalent energy minima based on σ-hole interactions using NCH, NH(3), OCHNH(2), and O-(CH(3))(2) as electron donor molecules, which were characterized using quantum chemistry tools. We believe that the results reported herein will have a significant impact on the fields of chemical biology, supramolecular chemistry, and biotechnology by describing for the first time σ-/π-hole interactions involving Co in biological systems, which are often overlooked by traditional coordination chemistry.