Abstract
The lock-and-key concept is discussed with respect to necessary extensions. Formation of supramolecular complexes depends not only, and often not even primarily on an optimal geometric fit between host and guest. Induced fit and allosteric interactions have long been known as important modifications. Different binding mechanisms, the medium used and pH effects can exert a major influence on the affinity. Stereoelectronic effects due to lone pair orientation can lead to variation of binding constants by orders of magnitude. Hydrophobic interactions due to high-energy water inside cavities modify the mechanical lock-and-key picture. That optimal affinities are observed if the cavity is only partially filled by the ligand can be in conflict with the lock-and-key principle. In crystals other forces than those between host and guest often dominate, leading to differences between solid state and solution structures. This is exemplified in particular with calixarene complexes, which by X-ray analysis more often than other hosts show guest molecules outside their cavity. In view of this the particular problems with the identification of weak interactions in crystals is discussed.
Highlights
After Emil Fischer coined the lock-and-key picture for the reaction between enzymes and substrates [1], it became a leading concept for the understanding of intermolecular interactions with proteins, and later for the rational design of drugs
With the advent of supramolecular chemistry the idea gained an enormous momentum, as chemists began to synthetize a large variety of host compounds for practically all possible target guest molecules occurring in nature or in the environment
Hydrophobic Interactions beyond the Lock-and-Key Picture. At first sight it seems that hydrophobic forces, which were traditionally ascribed to an entropy advantage gained by association between lipophilic molecules and subsequent liberation of water molecules, should not lead to particular deviations from the lock-and-key principle: the larger and closer the contact between a host cavity and a guest, the larger will be the number of liberated water molecules
Summary
After Emil Fischer coined the lock-and-key picture for the reaction between enzymes and substrates [1], it became a leading concept for the understanding of intermolecular interactions with proteins, and later for the rational design of drugs. Molecular clips and tweezers bear a highly negative surface potential inside; the binding of the preferred guest molecules such as, e.g., NAD+ is dictated more by Coulombic forces than by exact fitting [11]. Ancillary ligands such as tetraaza-cyclododecanes can increase the positive charge at bound highly polarizable lanthanide ions, thereby leading to enhanced sensing affinities towards anions [12]. Reprinted from [13] with permission from VCH/Wiley
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