THE NATURE OF EXZYME ACTIVE CENTERS 203 



p. 123). Alteration of the ionic strength, pH, or dielectric constant and the 

 introduction of substances (e.g. urea) that can form hydrogen bonds with 

 the polypeptide chain may influence the helical structure or the fraction 

 of the protein in this configuration. 



It is interesting to admit the possibility that protein flexibility is involved 

 in interactions with some molecules and that a rigid configuration is by 

 no means necessary. The ability of serum albumin to bind many types 

 of substance has been attributed to a high degree of flexibility of the pro- 

 tein structure (Klotz and Urquhart, 1949a). When an inhibitor approaches 

 an enzyme surface it is possible that occasionally there is a mutual orien- 

 tation produced by the interaction forces so that the final state will be 

 maximaUy stable. 



Relationships of Active Site Structure to Inhibition 



The importance of some of the concepts discussed in this section to en- 

 zyme inhibition may conveniently be summarized. 



(A) Since an active center may contain several individual sites on which 

 dissociable acceptors, activators, or coenzymes are bound, it is possible for 

 an inhibitor to interfere in the binding of any component or to disturb the 

 coordination between the sites. 



(B) The fact that an individual site can be reasonably complex and com- 

 prise numerous groups makes it possible for the inhibitor to block the reac- 

 tion by several mechanisms; one might state that the more complex the 

 site, the greater will be the opportunity for inhibition. 



(C) In considering the forces and energies of interaction between an en- 

 zyme and an inhibitor, the presence of multiple groups makes it necessary 

 to take into account a variety of interactions of different types. Simplifi- 

 cation of the picture is often mandatory for progress but the approxi- 

 mate nature of the treatment should never be forgotten. 



(D) In those situations where an accurate fit of the substrate to the active 

 site is necessary over an extended area, an inhibitor related structurally 

 to the substrate usually must conform fairly closely to this pattern and 

 deviations from the substrate structure will result iii much reduced binding. 

 However, where only a portion of the substrate molecule need fit the active 

 site, or the intermolecular forces are sufficiently strong to obviate the ne- 

 cessity of close fit, substances related to the substrate in various ways 

 will be more likely to be bound and produce inhibition. 



(E) Flexibility of the protein at the active site will allow interaction 

 with a greater range of inhibitor molecules and the assignment of rigid 

 active site structures cannot be made so readily. 



