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 A (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

Charge assisted

H

\

/N"

H—

O

N-

H—

— O

/

H

Charge-assisted "salt bridge"

FIGURE 1.6 Examples of different types of hydrogen bonds observed in ligand-protein complexes.

FIGURE 1.6 Examples of different types of hydrogen bonds observed in ligand-protein complexes.

(Figure 1.2) and that hydrogen bonding is an exchange process. Before formation of the ligand-protein complex (left-hand side in Figure 1.2) the polar functional groups of the ligand, the polar amino acid residues and C=O and NH backbone groups in the protein are engaged in hydrogen bonding with surrounding solvent water molecules. In the ligand-protein complex (right-hand side in Figure 1.2) these hydrogen bonds to the solvent are replaced by hydrogen bonds between the ligand and the protein. The net effect of this hydrogen bond exchange process is the difference in free energy between hydrogen bonding to water and to the protein. As a consequence of this exchange process, a substituent that is hydrogen bonded to water molecules in the aqueous phase, but that is buried in the binding cavity but not hydrogen bonded to the protein (an unpaired hydrogen bond) is strongly unfavorable for binding. It has been shown that the energy cost for an unpaired hydrogen bond is ca. 4 kJ/mol for a neutral substituent and ca. 16 kJ/mol for a charged substituent. This is equivalent to a loss of affinity by a factor of 5 and 500, respectively.

The successful formation of a hydrogen bond in the binding cavity has been estimated to contribute to the binding affinity by 2-6.5 kJ/mol (corresponding to an affinity increase by a factor of

2-13) for a neutral bond and by 10-20 kJ/mol (equivalent to a 50- to 500-fold increase in affinity) for a charge-assisted hydrogen bond or a salt bridge.

Was this article helpful?

0 0

Post a comment