288 6. INTERACTIONS OF INHIBITORS WITH ENZYMES 



which leads to a discrepancy of 0.56 kcal/mole, close to the value given by 

 Bernhard. Bergmann (1958) considered the energy reduction in removing a 

 methyl group to result from the greater hydration of the cationic group. 

 It was felt that the methylated nonhydrated ammonium ion could approach 

 the anionic site more closely than the hydrated forms. It is likely that dis- 

 tance of approach is not the only factor but the effect of hydration must 

 be important and is perhaps responsible for the 0.56-0.7 kcal/mole deficit 

 noted above. 



The increased binding of N(C2ll5)4'^ over N(CIl3)4^ must be accounted 

 for on the basis of greater dispersion energy. Since the radius of the former 

 ion is greater, the ion-ion interaction energy must be somewhat less; cal- 

 culation leads to 0.25 kcal/mole less based on a 1 A increase in radius. This 

 must be added to the relative AF, giving — 1.01 kcal/mole for the extra 

 dispersion energy, which is equivalent to — 0.34 kcal/mole for each — CHg— 

 group, a very reasonable value. The increased binding of the dimethyl- 

 propyl over the trimethylammonium ion should be due to the dispersion 

 energy from — CH.jCIIa— , which would be predicted to be 2x0.34 = 

 0.68 kcal/mole, which compares with the experimental value of 0.78 kcal/ 

 mole. The failure of the ethanol group to be bound more tightly than the 

 propyl group indicates that no hydrogen bond is formed by the hydroxyl 

 group with the protein. 



Dispersion Interaction of Substituted Halogen Groups 



If the plasma cholinesterase contains no anionic group at the active 

 site, attraction between the enzyme and substrate must be due to dipolar 

 and dispersion forces, and the magnitude of these forces will depend on the 

 dipole moments and polarizabilities of the substrates. In order to test 

 this, Adams and Whittaker (1950) compared the affinities of the enzyme 

 for esters of chloroacetate and bromoacetate with similar esters of pro- 

 pionate. 



R-O-CO-CH2-CH3 R-O-CO-CH2-CI R-O-CO-CHj-Br 



The results are shown in Table 6-24. Their calculations show that dispersion 

 forces can account for the different binding energies with the plasma cho- 

 linesterase. The calculated energy values, obtained from Table 6-19 agree 

 almost exactly with the experimental figures. 



The energy differences for the erythrocyte enzyme are more difficult 

 to interpret. Adams and Whittaker assumed that the increased energy 

 difference over the plasma enzyme was due to the fact that the erythrocyte 

 enzyme possessed an anionic group which would interact with dipoles and 

 induced dipoles in the substituted groups. However, the relative changes 

 for the CI and Br groups are in the opposite direction from that expected 



