304 6. INTERACTIONS OF INHIBITORS WITH ENZYMES 



It has been frequently stated that accuracy of fit is particularly important 

 in dispersion interactions, since the energy varies with d~^, whereas in 

 ion-ion interactions, for example, where the energy varies with d~^, the 

 fit would not be so important. This has only an element of truth in it. In 

 the first place, such considerations have often neglected the effect of the 

 repulsion forces in modifying the slope of the energy-distance curve; for 

 dispersion interactions the repulsion forces the curve to flatten out at 

 relatively lower values of the energy (in absolute figures) than for ion-ion 

 interactions, and thus the slope predicted at the equilibrium distance 

 without repulsion effects is not applicable. Secondly, the index of fit may 

 be larger for ion-ion interactions than for dispersion, which may be seen in 

 Fig. 6-20. It is true that in the ion-ion interaction a greater equilibrium 

 energy is involved and that, considering the peaks in the curves, {dcpj 

 ^^^)maxlVe = O-'^O for the ion-ion case whereas {d(pldd)y^^^Jcp^ = 0.64 for dis- 

 persion, but the importance for inhibition usually lies in the total energy 

 change upon variation of separation distance, not the change relative to 

 the maximal interaction energy. Actually the index of fit will depend on 

 a number of factors, as indicated in Eq. 6-119, including the values of ^ 

 and B as well as the power dependencies on the distance. Thus the index 

 of fit will be greater for a hexyl chain lying in a slit than for a single methyl 

 group, since the value of B will be greater in the former. 



EFFECTS OF ALTERATION OF STRUCTURE ON MOLECULAR 



PROPERTIES 



It is a very common practice in metabolic and enzyme studies to alter 

 the structure of a substrate or known inhibitor to determine the modifi- 

 cation in the behavior. Thus a useful way of finding specific inhibitors is 

 to modify a substrate in different ways, with the aim to produce a sub- 

 stance which retains the ability to interact with the active site but which 

 will not be catalytically acted upon. Determination of the topography 

 of the active site often involves the use of series of related compounds in 

 order to characterize and localize reactive or binding groups on the enzyme 

 surface. Some insight can often be obtained into the mechanism of an in- 

 hibition and of the forces occurring in the binding by the use of inhibitors 

 differing from one another only by discrete groups or structures. It is there- 

 fore of considerable importance to inquire into the changes in molecular 

 properties that may occur upon such structural modification and the 

 relationships of these changes to the interpretation of inhibition studies. 



Possible Ways in Which Structural Modification May Be Made 



The changes in structure most commonly used in inhibition work may 

 be conveniently classified in the following three types. 



