Reaction-Free Energies\nfor Complexation of Carbohydrates\nby Tweezer Diboronic Acids

The accurate calculation of reaction-free\nenergies (Δ<sub>r</sub><i>G</i>°) for diboronic\nacids and carbohydrates\nis challenging due to reactant flexibility and strong solute–solvent\ninteractions. In this study, these challenges are addressed with a\nsemiautomatic workflow based on quantum chemistry methods to calculate\nconformational free energies, generate microsolvated solute structural\nensembles, and compute Δ<sub>r</sub><i>G</i>°.\nWorkflow parameters were optimized for accuracy and precision while\ncontrolling computational costs. We assessed the accuracy by studying\nthree reactions of diboronic acids with glucose and galactose, finding\nthat the conformational entropy contributes significantly (by 3–5\nkcal/mol at room temperature). Explicit solvent molecules improve\nthe computed Δ<sub>r</sub><i>G</i>° accuracy\nby about 4 kcal/mol compared to experimental data, though using 13\nor more water molecules reduced precision and increased computational\noverhead. After fine-tuning, the workflow demonstrated remarkable\naccuracy, with an absolute error of about 2 kcal/mol compared to experimental\nΔ<sub>r</sub><i>G</i>° and an average interquartile\nrange of 2.4 kcal/mol. These results highlight the workflow’s\npotential for designing and screening tweezer-like ligands with tailored\nselectivity for various carbohydrates.