Can the Structure of the Hydrophobic Core Determine the Complexation Site? - Identification of Ligand Binding Site and Protein-Protein Interaction Area - page 47

Δ H profile and volumetric hydrophobicity distribution in 3DRC. ( a ) Δ H pro fi le, with
ligand-binding residues tagged in pink ; ( b ) 3D representation of 3DRC with attached ligand ( dark
blue ). Red areas indicate residues with high Δ H values - their placement in close proximity to the
ligand suggests that such residues are involved in generating binding pockets

Fig. 3.3

Δ H reaches local maxima suggests that these
residues are associated with localized hydrophobicity deficiencies. By the same
token, residues for which

Analysis of residues for which

Δ H reaches local minima point to areas of excess

hydrophobicity.
Hydrophobicity deficiencies may be caused by the proximity of ligand-binding
pockets while residues with excess hydrophobicity (local minima in the Δ H pro fi le)

permit protein-protein interactions and can therefore be responsible for protein
complexation (if they are located on the surface of the protein).
Another question may be asked at this point: how can the locations of such
anomalous residues in the protein's volumetric structure be determined? In order to
better illustrate this issue we can depict the distribution of hydrophobicity in a
folded protein using a color gradient (Fig. 3.3 ). Red areas indicate high

Δ H values

Δ H minima. Green residues are consistent with
theoretical predictions with respect to hydrophobicity.
Figure 3.3 also suggests that at least in some proteins the structure of the hydro-
phobic core is accordant with the theoretical model and that the factor which likely
triggers distortions in the core structure is the presence of the ligand.
The following questions should now be posed:

while blue areas correspond to

1. Has the ligand attached to the protein molecule by compensating for its hydro-
phobicity de fi ciencies?
2. Can the ligand be responsible for irregularities which emerge in the protein structure
during folding and which ensure high specificity of the resulting binding pocket?

Δ H maxima in the hydrophobicity profile
should point to the binding sites of hydrophobic ligands. Moreover, by binding to the
protein molecule the ligand should compensate for its hydrophobicity deficiencies,
resulting in a perfect “oil drop” structure (as predicted by the 3D Gauss function).

If the former assumption holds then