258 6. INTERACTIONS OF INHIBITORS WITH ENZYMES 



cules around ions. There has been no general agreement as to the directions 

 in which the water molecules around an anion lie. It has been often assumed 

 that a water molecule takes up a position wherein a hydrogen atom lies on 

 a line between the ion and the oxygen atom, but as Buckingam (1957) 

 pointed out, this means that the water dipole is oriented about 52° from 

 the ionic electric force field, as in orientation (A). Buckingahm prefers 



H H 



/ \ 



X- H O X- O 



/ 

 H 



(A) (B) 



the orientation (B) in which the maximal interaction with the water di- 

 pole can occur. The hydrogen ion presents a special case because a proton 

 is probably associated with one water molecule as H3O+ and it is this ion 

 that is hydrated, not only because of the electrical field but as the result 

 of hydrogen bonding. Also the orientation of water molecules around an 

 hydroxyl ion is probably asymmetrical because of the different positions 

 the water molecules must assume to form hydrogen bonds (Ackermann, 

 1957). 



Hydration of Proteins 



Water is associated with protein molecules in solution in a variety of 

 ways inasmuch as the protein surface is made up of regions of differing 

 properties. There are both structure-forming and structure-breaking re- 

 gions, and there are groups that will be hydrated because of their ionic 

 nature and others because of their ability to form hydrogen bonds with 

 the water. In summary, the water near the protein or enzyme surface will 

 be in a different state than the water in the bulk phase. The water struc- 

 ture around a protein will depend particularly upon the amino acid compo- 

 sition and the pH Ijecause these will determine the ionic state of the pro- 

 tein. Experimental evidence for an oriented water structure around pro- 

 teins has been obtained by Klotz (1958) who attached the ionizing azo- 

 mercurial group, — Hg— cp — N=N— cp— N(CH3)2, to several proteins and 

 found that the ionization was decreased (i.e., it was more difficult for a 

 proton to reach the — N(CH3)2 group to produce a positively charged 

 group). He attributed this to the icelike structure of the water surrounding 

 the proteins. In the case of serum albumin, this cage structure becomes 

 especially important below a pH of 4.2, the extent and rigidity of the ice- 

 like structure increasing. It is obvious that the interaction of any mole- 

 cules with enzymes must be determined to some extent by this water en- 

 velope and that the ability of a molecule to bind to an enzyme may de- 

 pend on whether the molecule can disrupt the water structure. 



