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 exhibiting exceptional selectivity. Elucidating the molecular basis of this selectivity could be valuable for the rational design of receptors for other carbohydrate targets. In this study, we investigate the binding dynamics of GluHUT through extensive molecular dynamics simulations and enhanced sampling techniques, focusing on its complexation with glucose, galactose, and fructose in water. Umbrella sampling along a predefined reaction coordinate provides an atomistic view of the entire binding process, revealing the thermodynamic determinants of selectivity and the corresponding free energy profiles. Detailed analyses of hydrogen bonding networks, noncovalent interactions, and solvent reorganization demonstrate that even minor structural variations among sugars can lead to significant differences in binding affinity. These findings, together with the computed binding free energies that qualitatively agree with experimental trends, provide a mechanistic rationale for GluHUT's remarkable specificity toward glucose.