Biomolecular Recognition: The Current Challenge - Dynamic Force Spectroscopy and Biomolecular Recognition - page 31

disease, a replacement of a lysine with a valine resulted in 2.2-fold decrease of the
dissociation rate between von Willebrand factor and GPIb αligand under flow [114].
In another study, the replacement of an alanine with a valine in a TCR chain resulted
in a binding free energy change of about 3 k B T [198]. The authors emphasized that
the affinity changes displayed cooperative rather than additive behavior when they
compared the effect of separate or concomitant changes of amino acids at several
positions [198]. An important point is that in some cases binding properties were
changed following an alteration of an amino acid residue located out of the contact
area as identified on the basis of crystallographic studies.
Is a particular type of interaction favored in biologically relevant ligand-receptor
couples? As recently emphasized [22], the role of electrostatics on binding affinities
remains controversial, but a study of nearly 300 protein complexes led the authors
to conclude that in most cases electrostatic forces did not strongly contribute to
binding affinity. Indeed, there is a balance between desolvation energies required
for molecular contact and attraction energies if there is a match between charges
born by opposite surfaces. There are, however, some examples where electrostatic
charges contribute significantly to binding efficiency. Electrostatic interactions con-
tributed by four glutamic acid residues was estimated to account for 32% of the
binding energy in the thrombin-hirudin couple [181]. Also, electrostatic interactions
might be useful to give a proper orientation to approaching ligands and receptors,
a phenomenon denominated as electrostatic steering [109]. More recently, alanine
scanning was used to study the influence of individual aminoacids on the binding to
a talin oligopeptide of a 25-mer sequence of the membrane-proximal tail of several
integrins. A general finding was that alanine replacement of acidic groups increased
binding efficiency, while alanine replacement of basic groups slightly reduced this
interaction [78], thus supporting the influence of charges in some cases of molecular
interactions.
Further, there is much evidence supporting the view that hydrophobic bonds are
responsible for an important part of binding affinities [39] [44] [50]. In a compilation
of 75 ligand-receptor complexes of known atomic structure, the fraction of apolar
atoms was about 56%. Hydrophobic bonds might thus contribute on the order of
several tens of k B T to the binding free energy, based on the aforementioned estimates
of contact areas and solvation free energies.
The average surface density of hydrogen bonds was estimated as one per 170 A 2
in the series of 75 complexes mentioned above [44]. A recent study of the effect
of a number of mutations on the interaction between a triacylated lipopeptide and a
pattern recognition receptor led the authors to emphasize the importance of a network
of hydrogen bonds in binding [104].
In conclusion , despite a number of studies based on a growing number of 3D
structures, recognition interfaces between ligands and receptors did not display uni-
versal specific features, and it seems accepted that binding is a variable blend of polar
and apolar interactions that will result in sufficient binding energy provided there is
a proper match in the shape and charge distribution of interacting surfaces.