Biomedical Engineering Reference
In-Depth Information
AChBP. The binding displays a cation-
π
interaction between the ammonium group in nicotine and
the indole ring system of Trp143.
1.3.4
D
G
hydrophob
—T
HE
H
YDROPHOBIC
E
FFECT
The hydrophobic effect is a concept used to describe the tendency of nonpolar compounds to trans-
fer from water to an organic phase, for example, a lipophilic region of a protein. When a lipophilic
compound is inserted into water it changes the dynamic network of hydrogen bonds between water
molecules in pure liquid. It creates a new interface in which water molecules around the lipo-
philic compound assume a more ordered arrangement than bulk water. This results in a decrease
in entropy. Formation of a ligand-protein complex displaces the ordered water from the ligand and
the protein into bulk water, as shown in Figure 1.10. The increased “freedom” of movement of the
released water molecules gives an increase in entropy (
Δ
S
) and, according to Equation 1.3, a more
G
—an increase in afi nity.
The magnitude of the hydrophobic effect is related to the area of hydrophobic surface that is bur-
ied in the binding cavity. Estimates, based on measurements of solvent transfer and ligand binding,
range between 0.1 and 0.24 kJ/Å
2
mol. The burial of a methyl group of ca. 25 Å
−2
is thus expected
to result in an afi nity increase by a factor of 3-10. In cases of a more perfect i t between a methyl
group and the protein, the afi nity increase may be even larger.
Analysis of ligand-protein interactions and attempts at ligand design often focus on hydrogen
bonding and other electrostatic interactions. However, in many cases even strong hydrogen bond
interactions may favorably be replaced by hydrophobic interactions. An example of this is shown in
Figure 1.11. The inl uenza neuraminidase inhibitor
1.1
binds to the protein with an afi nity (IC
50
) of
negative
Δ
Δ
S
>0
FIGURE 1.10
The hydrophobic effect.
O
Glu
-
Glu
O
O
-
O
H
O
H
O
O
HO
NHAc
NHAc
O
HO
2
C
NH
2
HO
2
C
NH
2
1.1
IC
50
= 150 nM
1.2
IC
50
= 1 nM
FIGURE 1.11
Inl uenza neuraminidase inhibitors.
