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

The accurate calculation of reaction-free
energies (ΔrG°) 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 ΔrG°.
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 ΔrG° 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
ΔrG° 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.

精准计算二硼酸与碳水化合物的反应标准吉布斯自由能变（ΔrG°）颇具挑战，这一难题源于反应物的柔性以及溶质与溶剂间的强相互作用。本研究基于量子化学方法构建了一套半自动工作流，通过计算构象自由能、生成微溶剂化溶质结构集合并最终计算ΔrG°，解决了上述难题。该工作流的参数在兼顾计算成本的前提下，针对准确性与精度进行了优化。我们通过研究二硼酸与葡萄糖、半乳糖的三类反应评估了该方法的准确性，发现构象熵的贡献十分显著（室温下可达3~5 kcal/mol）。与实验数据相比，显式溶剂分子可使计算所得ΔrG°与实验值的偏差降低约4 kcal/mol，但当使用13个及以上水分子时，会降低计算精度并增加计算开销。经过微调后，该工作流展现出优异的准确性：与实验测得的ΔrG°相比，其绝对误差约为2 kcal/mol，平均四分位距为2.4 kcal/mol。本研究结果凸显了该工作流在设计、筛选针对不同碳水化合物的定制选择性镊子状配体方面的应用潜力。