Reviews in Computational Chemistry Volume 18

protein
N
H
H O H
protein
CH 3
H O H
H
O
N
H
H
+ +
O
O
ligand protein-ligand
complex
H
O
H
CH3 + +
CH 3
H
O
H
H O H
H
O
H
H O H
in the quantitative treatment of protein–ligand interactions: providing an
accurate description of the role of water molecules (Figure 2). It has been
shown, by comparing the binding affinities of ligand pairs differing by just
one hydrogen bond, that the existence of an individual hydrogen bond can
even be adverse to binding. 38 Charge-assisted hydrogen bonds are stronger
than neutral ones, but this enhancement in binding is paid for by higher
desolvation penalties. The electrostatic interaction of an exposed salt bridge
is worth as much as a neutral hydrogen bond (5 1 kJ/mol according to
Ref. 39), and the same interaction in the interior of a protein can be significantly
larger. 40
The experimental determination of H and S sometimes yields surprising
results, as, for example, in the thermodynamics of hydrogen-bond formation
in the complex of FK506 or rapamycin with FK506-binding protein
(FKBP). 34 Binding to the wild-type and to the mutant Tyr 82 ! Phe 82 was
CH 3
ligand protein-ligand
complex
Introduction 47
Figure 2 Role of water molecules in hydrogen bonds (upper part) and lipophilic
interactions (lower part). In the unbound state (left side), the polar groups of the ligand
and the protein form hydrogen bonds to water molecules. These water molecules are
replaced upon complex formation. The hydrogen-bond inventory (total number of
hydrogen bonds) does not change. In contrast, the formation of lipophilic contact
increases the total number of hydrogen bonds due to the release of water molecules from
the unfavorable lipophilic environment.