Chemistry Reference
In-Depth Information
with
N
-acetyllactosamine [4]. The thermodynamic analysis evidences the existence
of enthalpy-entropy compensation, as typically observed for protein-carbohydrate
interactions [16]. Thus, although changes in enthalpy and entropy may be consid-
erable, the net free energy of binding or, in other words, the binding affi nity is
relatively small, in the millimolar range, as commonly observed for the binding
of mono- or disaccharides by lectins.
The affi nity for oligosaccharides can be increased up to the micromolar
range as a result of the binding of several sugar units to extended binding sites
in proteins. Accommodation at the secondary binding subsites is also driven
by a favorable enthalpy, but the entropy cost may be smaller because the
overall motion and conformational freedom of the oligosaccharide has already
been restricted, at least in part, upon binding at the primary binding subsite.
Multivalency can also result in considerably higher binding affi nities in protein-
carbohydrate interactions [16-18]. The simultaneous binding of clustered binding
sites in carbohydrate-binding proteins to multivalent ligands, as those presented
on cell surfaces, can increase the affi nity up to nanomolar levels (please see
Chapters 17-19 for different ways of clustering carbohydrate recognition domains
in lectins, and Chapter 4 for details on synthetic polyvalent ligands). After the
fi rst contact is established, ligand binding to the other binding sites may be
facilitated by spatial vicinity and the entropy cost of these interactions is progres-
sively smaller. Furthermore, the fi rst contact itself may be affected by a smaller
entropic penalty compared to a monovalent interaction if the particular presenta-
tion in the multivalent ligand restricts the fl exibility and freedom of the
carbohydrate.
13.5
Conclusions
The important role played by protein-carbohydrate interactions in many biomedi-
cally relevant processes makes them interesting targets for the development of
new carbohydrate-based therapeutics. A rational design of ligands with improved
binding affi nity should be grounded on the understanding of the atomic features
and forces governing the binding thermodynamics. A detailed knowledge of the
carbohydrate-binding site architecture and the sugar groups involved in the rec-
ognition may facilitate the optimization of the binding enthalpy by increasing the
number and strength of hydrogen bonds and van der Waals contacts between the
protein and the sugar. On the other hand, elucidation of the conformational prop-
erties of the sugar in the free and bound states may help to decrease the entropic
penalty of the binding by designing ligands with reduced fl exibility and maximum
complementarity with the protein's binding site. Finally, the entropy gain associ-
ated with desolvation of non-polar surfaces could be exploited by tailoring hydro-
phobic ligands.
