Abstract:
Sulfur-mediated chalcogen (Ch-) bonds are known to play critical roles in protein structure and stability. However, their role in substrate recognition by enzymes is unknown. Here, we show that the binding of the substrate methionine to the enzyme methionyl-tRNA synthetase involves a σ-hole-mediated Ch-bond. Through the geometry of the interaction and features of the electron density distribution, we establish the interaction as a bona fide Ch-bond. Disruption of the Ch-bond by mutagenesis results in loss of substrate binding. Using selenomethionine, we show that the strength of the Ch-bond can be tuned by changing the polarizability of the Ch-atom. ONIOM (QM/MM) calculations reveal that substituting sulfur with selenium leads to a shorter interaction distance and a more linear n → σ* approach, rationalizing the enhanced binding affinity observed with selenium. Our study shows that σ-hole-mediated S···O and Se···O Ch-bonds, which are analogous to hydrogen and halogen bonds, can facilitate substrate binding and molecular recognition.