256 6. INTERACTIONS OF INHIBITORS WITH ENZYMES 



of molecules. The association energy depends on the enthalpy and entropy 

 changes occurring during modification of this water structure. Pure water 

 possesses structure in the statistical sense; that is, at any time a certain 

 fraction of the water molecules will be bound to neighboring molecules 

 to form small regions of tetrahedral orientation as in ice. Various terms have 

 been used in discussing water structure: the temporary structural aggre- 

 gates may be called " frozen regions," " ice-bergs," or " microdomains 

 of ice," while the amount of structure in water under specified conditions 

 has been termed the " icelikeness " or " degree of polymerization." When 

 water molecules form icelike structures around small nonpolar molecules 

 or groups, these are frequently referred to as " cages." The association of 

 water molecules involves mainly hydrogen bonding, with other dipolar 

 interactions and small dispersion forces contributing to a lesser degree. 

 Water thus contains " flickering clusters " of various sizes and shapes, the 

 half-lives of these structures being perhaps of the order of lO^^'* to 10~^^ sec 

 (Frank and Wen, 1957). The fraction of the total water that is present in 

 these icelike clusters depends strongly on the temperature and this is 

 one factor that must be considered in the effects of temperature on inter- 

 actions in water. It was postulated that when two water molecules asso- 

 ciate, there is a tendency for neighboring molecules to become bonded and 

 participate in the structure, in a manner similar to crystallization. Converse- 

 ly, if the bond between two water molecules is broken in a formed cluster, 

 there will be a tendency for the cluster to break down or melt. This provides 

 a means by which localized effects on orientation can be propagated for 

 some distance in the solvent. 



When solute molecules are introduced into water, various effects may 

 be exerted on the water structure in the sense of altering the fraction of 

 the water that is in the icelike state or of changing the size and configu- 

 ration of the association clusters. The over-all effect may be an increase 

 or a decrease in the water structure. Substances that produce an increase 

 in the structure have generally been called structure formers and those that 

 cause a decrease in the structure have been called structure breakers. It 

 has been possible by studies on viscosity and entropy changes to classify 

 the common ions into these two categories (Frank and Wen, 1957). Thus 

 F~, OH", Ca^"^, and Mg^"^ are classed as structure formers and Cl~, Br", 

 I , NOg", S04~, and K"^ as structure breakers (K"*" exerting a very slight 

 effect). It is believed that multiply-charged cations, such as Mg^"*", pro- 

 duce a long-range ordering of the water structure, i.e., beyond the primary 

 hydration layer (Kaminsky, 1957), this being shown by studies on infrared 

 spectra, entropy changes, apparent molal heat capacities, and other pro- 

 perties. One might consider hydrated ions as providing nuclei for the for- 

 mation of icelike clusters, but the orientation of the water molecules around 

 the ions is usually not such as to fit into the usual water structure. An in- 



