Biomedical Engineering Reference
In-Depth Information
(a)
(b)
FIGURE 1.1
(a) Lock-and-key and (b) induced i t hypotheses.
by rotation about single bonds. In the protein, side-chain conformations as well as the backbone
conformation may adjust to optimize the ligand-protein interaction. The rapidly increasing number
of crystallographically determined 3D structures of proteins and ligand-protein complexes give
strong support to the induced i t hypothesis and this hypothesis is today generally accepted by the
scientii c community.
Studying an x-ray structure of a ligand-protein complex as visualized by modern computer
graphics hardware and software is fascinating and many useful details about ligand-protein interac-
tions can be learned from that. However, a study of a ligand-protein complex alone tells only a part
of the story of ligand-protein interactions. For instance, it does not give much information about the
strengths of the observed interactions. The purpose of this chapter is to discuss and give examples of
ligand-protein interactions in terms of basic physical chemistry. This chapter focuses on the under-
standing of the type and magnitude of different contributions to the strength of the ligand-protein
binding. This may provide answers to questions about what to expect in terms of afi nity for a given
drug if, for instance, a substituent in this drug is replaced by another one. It also provides a frame-
work for other chapters in this topic in which structure-afi nity relationships are being discussed.
1.2 DETERMINATION OF THE AFFINITY—THE TOTAL STRENGTH
OF THE LIGAND-PROTEIN INTERACTION
It is of utmost importance to understand the afi nity of a ligand for a protein and to keep in mind that
the afi nity is dei ned by the equilibrium between the unbound ligand and the unbound protein on
one side and the ligand-protein complex on the other, as shown in Figure 1.2. Thus, thermodynam-
ics governs the basic physicochemical principles of molecular recognition.
The afi nity of the ligand for the protein is given by the free energy difference (
G
) between
the ligand-protein complex (the right-hand side in Figure 1.2) and the “free” (unbound) ligand and
the “free” (unbound) protein (the left-hand side). Water plays an important role on both sides of the
equilibrium as will be discussed below.
It should be noted that the ligand exists as a mixture of conformations with different shapes on
the left-hand side but in a single well-dei ned conformation on the right-hand side. The protein con-
formation may also change between the left- and right-hand sides of the equilibrium and the water
structure is different on the two sides of the equilibrium.
Δ
