DISTORTION ENERGY 263 



Distortion of Enzyme Structure 



When the inhibitor fits into a cavity or crevice in the enzyme some ex- 

 pansion of the protein structure may occur. Dilatation of antibody pro- 

 tein to accommodate various haptenic groups has been discussed by Pauling 

 and Pressman (1915) although the energy involved could not be calculated. 

 Entropy data indicate a "loosening " of the enzyme structure on forming 

 the enzyme-substrate complex (Laidler, 1955 a). Little is known of inhibi- 

 tor-induced structural changes but a denaturation-like effect is postulated 

 to occur in the inhibition of bioluminescent enzymes by urethanes and 

 sulfonamides (Johnson et al., 1954). 



Distortion of Inhibitor Structure 



The bound inhibitor may exist in a strained state, that is in a configu- 

 ration different from that assumed in solution. Energy may be required 

 to alter bond angles or bring charged groups closer together. It is pos- 

 sible that in the inhibition of succinic dehydrogenase by malonate the 

 carboxylate groups are closer when the malonate is attached to the enzyme; 

 some bond strain might also occur if the enzyme cationic groups have a 

 separation distance different from the inter-carboxylate distance in mal- 

 onate. 



Distortion of Enzyme Side-Chains 



The amino acid side-chains at the surface of an enzyme probably possess 

 a degree of flexibility. In such cases they may assume positions around the 

 inhibitor to provide maximal contact. As an inhibitor molecule approaches 

 the enzyme surface these side-chains may swing around to equilibrium 

 configurations in which the potential energy is minimal. Some energy, 

 although usually quite small, may be necessary for the orientation, since 

 in the uninhibited enzyme the side-chains are in the most stable positions. 

 The flexibility of these side-chains may in part be determined by the 

 content of hydroxy amino acids, these forming hydrogen bonds with amino 

 or carboxyl groups and stabilizing their configuration. The absence of such 

 hydroxy amino acids has been postulated as explaining the ability of 

 seralbumin to bind many substances, this protein being more flexible than 

 most (Klotz and Urquhart, 1949 b). 



Distortion of Enzyme Charge Distribution 



It was pointed out by Kirkwood and Shumaker (1952) that the protein 

 surface possesses many groups capable of combining with protons and 

 that the distribution of charged groups can therefore fluctuate and will 

 depend on a number of factors. The protein surface may be considered as 

 having many possible charge distributions differing slightly in energy. 



