Free Energy Simulations on a Biomimetic Glucose Receptor: Understanding the Selectivity of GluHUT

Abstract

The bicyclic glucose receptor GluHUT represents a significant advance in supramolecular chemistry, binding glucose in water with an association constant of approximately 18,000 M ^-¹, and showing exceptional selectivity. Elucidating the molecular basis of this binding selectivity could be valuable for the rational design of receptors for other carbohydrate targets. The intricate dynamics of the binding process are probed here through extensive molecular dynamics (MD) simulations and enhanced sampling techniques to analyse the complexation of glucose, galactose, and fructose with GluHUT in water. Through performing umbrella sampling simulations, we obtained an atomic-level view of the entire binding event, revealing both the thermodynamic drivers of selectivity and the transition states involved. In-depth analysis of hydrogen bonding patterns, noncovalent interactions, and solvent reorganization showed that even minor structural variations in sugars can produce significant differences in binding affinity. These findings, supporting the computed binding free energies that closely mirror experimental data, provide a mechanistic rationale for GluHUT's remarkable specificity toward glucose.