Taste of sugar at the membrane: thermodynamics and kinetics of the interaction of a disaccharide with lipid bilayers.

Sugar recognition at the membrane is critical in various physiological processes. Many aspects of sugar-membrane interaction are still unknown. We take an integrated approach by combining conventional molecular-dynamics simulations with enhanced sampling methods and analytical models to understand the thermodynamics and kinetics of a di-mannose molecule in a phospholipid bilayer system. We observe that di-mannose has a slight preference to localize at the water-phospholipid interface. Using umbrella sampling, we show the free energy bias for this preferred location to be just -0.42 kcal/mol, which explains the coexistence of attraction and exclusion mechanisms of sugar-membrane interaction. Accurate estimation of absolute entropy change of water molecules with a two-phase model indicates that the small energy bias is the result of a favorable entropy change of water molecules. Then, we incorporate results from molecular-dynamics simulation in two different ways to an analytical diffusion-reaction model to obtain association and dissociation constants for di-mannose interaction with membrane. Finally, we verify our approach by predicting concentration dependence of di-mannose recognition at the membrane that is consistent with experiment. In conclusion, we provide a combined approach for the thermodynamics and kinetics of a weak ligand-binding system, which has broad implications across many different fields.