Molecular Recognition in Ligand–Protein Binding - Drug Design and Discovery - page 21

for example, nicotinic acetylcholine and GABA A receptors adjusts its position in response to the
size of the ligand (Figure 1.5). This has implications for the pharmacological proi le of the ligand
(see also Chapter 16).
Protein l exibility is a major challenge in structure-based drug design (see Chapter 2) and is cur-
rently the focus of much research.

1.3.3 D G polar —E LECTROSTATIC I NTERACTIONS AND H YDROGEN B ONDING

Δ G polar is the free energy change due to interactions between polar functional groups in the ligand

and polar amino acid residues and/or C O and NH backbone groups in the binding cavity of the

protein. In addition, indirect ligand-protein interactions via water molecules in the binding cavity
are frequently observed. These interactions include ion-ion, ion-dipole, and dipole-dipole interac-
tions, which are well described in topics on physical chemistry to which the reader is referred to for
details. The attraction between opposite charges or antiparallel dipoles plays an important role in
ligand-protein recognition.
The strength of any electrostatic interaction ( E polar ) is given by Coulomb's Law (Equation 1.6):

qq

polar = ij
ij

(1.6)

E

e r

where
q i and q j are integer values for ion-ion interactions and partial atomic charges (summed over the

participating atoms) for other polar interactions

ε is the dielectric constant

r ij is the distance between the charges

In Equation 1.6, it is important to note that the electrostatic energy E polar depends on the dielectric
constant ( ), which measures the shielding of the electrostatic interactions by the environment. The

dielectric constant of water is 78.4 (25°C). E polar is difi cult to quantify in proteins as

ε

is not uniform
throughout the protein but depends on the microenvironment in the protein. A value of about 4 is
often used for a lipophilic environment in the interior of a protein.
The relative strength of the different types of electrostatic interactions is ion-ion > ion-dipole >
dipole-dipole. Ion-ion interactions do not depend on the relative orientation of the interacting partners,
whereas ion-dipole and dipole-dipole interactions are strongly dependent on the relative orientation
of the interacting moieties. For instance, the interaction between antiparallel dipoles is attractive,
whereas that between parallel dipoles is repulsive.

ε

1.3.3.1 Hydrogen Bonds
A hydrogen bond X-H----Y may be described as an electrostatic attraction between a hydrogen
atom bound to an electronegative atom X (in ligand-protein interactions most often nitrogen or
oxygen) and an additional electronegative atom Y. The typical hydrogen bond distance is 2.5-3.0 Å
(as measured between the heavy atoms X and Y). A hydrogen bond is highly orientation dependent
with an optimal X-H----Y angle of 180°. Examples of different types of hydrogen bonds commonly
observed in ligand-protein complexes are shown in Figure 1.6.
Figure 1.7 displays the binding of ( S )-glutamate to the ligand-binding domain of the ionotropic
glutamate receptor iGluR2 featuring a “salt bridge” and a number of other charge-assisted hydrogen
bonds between the ligand and the receptor, and also between the ligand and water molecules in the
active site.
In order to understand the contribution of hydrogen bonding or other polar interactions to ligand
binding, it is crucial to keep in mind that the ligand-protein interaction is an equilibrium process