202 6. INTERACTIONS OF INHIBITORS WITH ENZYMES 



or crevice of the protein, the over-all binding energy will depend on the 

 fit and the possible modification in the size of the invagination. If a cavity 

 has to expand slightly to achieve maximal mutual contact with the reactant, 

 the energy involved in this dilatation must be considered. Indeed Pauling 

 and Pressman (1945) have calculated the amount of dilatation necessary 

 to accommodate various hapten groups in their interaction with antibodies. 

 Even the helix structure is not completely stable since it depends on hy- 

 drogen bonding and the electrostatic forces between the polypeptide chains. 

 Although the energy required to break such a hydrogen bond may be 8 

 kcal/mole, in water where hydrogen bonds are formed between the water 

 molecules and the polypeptide chain when the helix is disrupted, the over- 

 all energy required may be only 1.5 kcal/mole (Edsall and Wyman, 1958, 



{continued legend for Figure 6-2.) 



and the basic group: GH. Van der Waals' interactions probably also occur with the 

 methyl groups of the choline portion. (Wilson, 1954.) 



Acetylcholinesterase: This represents another concept of the active site wherein the 

 cationic head is held electrostatically by the surrounding carboxylate groups and the 

 ester link is subjected to tyrosine and histidine residues, the presence of a serine res- 

 idue at the active site being indicated by — CHjOH. Again, van der Waals' forces 

 are probably involved in the binding. (Bergmann, 1958.) 



Papain: The substrate is held mainly by electrostatic attraction and the susceptible 

 bond is placed spatially to the SH group so that an acyl intermediate is formed. (Kim- 

 mel and Smith, 1957.) 



Sarcosine oxidase: Three binding sites occur: (1) the interaction of the methyl group 

 with a hydrocarbon residue; (2) the interaction of the nitrogen atom with an electro- 

 philic group R; and (3) the electrostatic interaction of the carboxylate with a posi- 

 tively charged protein group. The sarcosine is thus held in a compact configuration. 

 (Frisell and Mackenzie, 1955.) 



Carhoxypeptidase: The substrate is initially bound to the zinc ion as a chelate with 

 three subsidiary binding groups, B^ interacting with the R, and the acyl groups, Bj 

 interacting with the Rj group, and B3 which interacts with Rj later in the reaction when 

 the carboxylate group has shifted. (Lumry and Smith, 1955.) 



Fumarase: The substrate is anchored mainly by one carboxylate group and the 

 molecule is exposed to the influence of two acidic groups that can donate and accept 

 H+, this being a type of acid-base catalysis. (Alberty, 1957.) 



In all cases the original representations of the active sites were intended to be only 

 indicative of the reaction mechanism and the known groups involved, and were not 

 meant to be accurate pictures of the true sites. Holes or crevices in the enzyme are not 

 necessary in all cases. In some cases the sites have been redrawn to conform to a 

 uniform presentation. 



