Chemistry Reference
In-Depth Information
Figure 13.5
Binding potential of different func-
tional groups in synthetic carbohydrate deri-
vatives. The arrows indicate the capacity to be
engaged in hydrogen bonding, as specifi ed in
the legend to Figure 13.1.
ment of the hydroxyl group as donor and/or acceptor.
O
- Methyl derivatives may
also help to probe the hydroxyl group activity and also provide information on the
steric requirements of the binding site, as the bulky methyl substituent may
engender steric hindrance. On the other hand, the methyl group may generate
favorable nonpolar interactions with the protein, thereby increasing the binding
affi nity. In this way, by systematic chemical mapping studies using an array of
synthetic ligand derivatives with different binding abilities, it is possible to dissect
the contribution of every sugar hydroxyl group to the binding, and even to delin-
eate the topology and distribution of nonpolar regions of the binding site. This
information can be extremely useful for tailoring superior ligands in drug design
processes. In addition, it helps to validate the list of interactions observed in the
crystal structures of protein-sugar complexes. The need for such a validation
originates from the frequent use of far-from-physiological conditions for crystalli-
zation and the potential infl uence of crystal packing on the structure.
13.2
Role of Water in Protein- Sugar Interactions
Water plays an essential role in protein- carbohydrate interactions [7] . In protein -
sugar complexes, water molecules are often found bridging sugar hydroxyl groups
with side-chains of the binding site, as mentioned above. In their uncomplexed
forms, both the protein and the sugar are fully solvated. As observed, for example,
in the crystal structure of the ligand-free form of human galectin-1 (here a C2S
mutant designed for increased stability against oxidative inactivation) (Figure
13.3 a), the carbohydrate -binding site is occupied by water molecules that stabilize
the orientation of the protein residues involved in sugar binding through a network
