Reaction-Free Energies for Complexation of Carbohydrates by Tweezer Diboronic Acids.

The accurate calculation of reaction-free energies (Δ r G °) for diboronic acids and carbohydrates is challenging due to reactant flexibility and strong solute-solvent interactions. In this study, these challenges are addressed with a semiautomatic workflow based on quantum chemistry methods to calculate conformational free energies, generate microsolvated solute structural ensembles, and compute Δ r G °. Workflow parameters were optimized for accuracy and precision while controlling computational costs. We assessed the accuracy by studying three reactions of diboronic acids with glucose and galactose, finding that the conformational entropy contributes significantly (by 3-5 kcal/mol at room temperature). Explicit solvent molecules improve the computed Δ r G ° accuracy by about 4 kcal/mol compared to experimental data, though using 13 or more water molecules reduced precision and increased computational overhead. After fine-tuning, the workflow demonstrated remarkable accuracy, with an absolute error of about 2 kcal/mol compared to experimental Δ r G ° and an average interquartile range of 2.4 kcal/mol. These results highlight the workflow's potential for designing and screening tweezer-like ligands with tailored selectivity for various carbohydrates.