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 concanava lin-A. The 2 Angstrom structure of glucoside bound concanavalin-tl is reported and compared with the 2 Angstrom structure of the mannoside c omplex. The interaction energies of the substrate in each crystallogra phic subunit were calculated by molecular mechanics and found to be es sentially the same for both sugars. Further energy minimisation of the active site region of the subunits did not alter this conclusion. Inf ormation from crystallographic B-factors was interpreted in terms of m obility of the sugars in the combining site. Molecular dynamics (MD) w as employed to investigate mobility of the ligands at the binding site s. Switching between different binding states was observed for mannosi de over the ensemble in line with the crystallographic B-factors. A ca lculated average interaction energy was found to be more favourable fo r mannoside than glucoside, by 4.9 +/- 3.6 kcal mol(-1) (comparable wi th 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 demonstr ates the difficulty in relating structure to thermodynamic properties, but suggests that dynamic models are needed to provide a more complet e picture of ligand-receptor interactions.