Probing Weak Halogen Bonding in Aqueous Solution

Noncovalent interactions are as important for chemistry and biology as they are difficult to characterize. They determine the 3D structure of biopolymers, the binding mode and affinity of drug candidates, and the mechanisms and kinetics of enzymatic reactions and molecular recognition events, to name a few examples of processes that take place in aqueous solution. A single noncovalent force, with its inherent weakness, yields transient low-affinity complexes that are especially challenging to detect in dilute solutions, especially in polar and protic solvents that offer competing interactions, such as water. Using weak halogen bonding (<20 kJ mol^-1) as an example, we showcase a strategy to characterize very weak interactions in dilute aqueous solution using NMR spectroscopy. We characterize the relative strength of a set of weak iodine and bromine-centered halogen bonds by describing their ability of stabilizing a β-hairpin motif, whose population was quantified using NOE- and J-coupling-based ensemble analysis, and describe the geometry of the halogen bond based on bond orientations with ¹H-¹³C residual dipolar couplings. Density functional theory calculations corroborate the experimentally observed trends. Our work presents one of the very first detailed experimental characterizations of halogen bonding in aqueous solution and a methodology that allows systematic assessment of this interaction in the solvent most relevant for drug discovery. Due to the modularity of the presented model system, the strategy is easily transferable to the characterization of other single, weak noncovalent interactions, such as hydrogen, chalcogen, pnictogen, and tetrel bonds, Coulomb forces, or π interactions in dilute aqueous solution.