X-ray and molecular dynamics studies of concanavalin-A glucoside and mannoside complexes - Relating structure to thermodynamics of binding

Crystallographic and computational methods have been used to study the binding of two monosaccharides (glucoside and mannoside) to concanavalin-A. The 2 Angstrom structure of glucoside bound concanavalin-tl is reported and compared with the 2 Angstrom structure of the mannoside complex. The interaction energies of the substrate in each crystallographic subunit were calculated by molecular mechanics and found to be essentially the same for both sugars. Further energy minimisation of the active site region of the subunits did not alter this conclusion. Information from crystallographic B-factors was interpreted in terms of mobility of the sugars in the combining site. Molecular dynamics (MD) was employed to investigate mobility of the ligands at the binding sites. Switching between different binding states was observed for mannoside over the ensemble in line with the crystallographic B-factors. A calculated average interaction energy was found to be more favourable for mannoside than glucoside, by 4.9 +/- 3.6 kcal mol(-1) (comparable with the experimentally determined binding energy difference of 1.6 +/- 0.3 kcal mol(-1)). However, on consideration of all terms contributing to the binding enthalpy a difference is not found. This work demonstrates the difficulty in relating structure to thermodynamic properties, but suggests that dynamic models are needed to provide a more complete picture of ligand-receptor interactions.