CHAPTER 6 



INTERACTIONS OF INHIBITORS 

 WITH ENZYMES 



Inhibition of an enzyme reaction is most frequentlj^ due to the binding 

 of the inhibitor at certain regions on the enzyme protein. The present 

 chapter will be mainly concerned with the forces and energies involved in 

 these interactions and the relationships between enzyme inhibition and the 

 structural characteristics of inhibitor and enzyme. Reaction of the inhi- 

 bitor with the enzyme may be chemical in nature (with the formation of 

 covalent bonds) or it may involve the less specific types of attractive forces 

 that exist between molecules. Attention will be primarily directed to these 

 nonchemical interactions of relatively lower energy and the instances of 

 specific chemical reaction will be discussed in connection with the inhibi- 

 tors where they occur. It is believed that enzymology in the future will be 

 much concerned with enzyme surfaces, particularly with the active centers, 

 and the forces between these regions and other molecules surrounding the 

 enzyme in solution. This is a conceptually new micro-world with new di- 

 mensions for our thinking, in which it is necessary to visualize complex 

 fields of electrical intensity in addition to the blurred contours of the mol- 

 ecules, where every atom or group reacts in some manner with every other 

 atom or group as molecules approach one another and where the most 

 stable position of minimum potential energy is determined by the balance 

 of the various attractive and repulsive forces. 



Knowledge and theory at this molecular level are not adequate at pres- 

 ent to form the basis for a comprehensive approach to an accurate eval- 

 uation of intermolecular forces between complex molecules in solution. 

 But enough has been accomplished so that a tentative beginning can be 

 made, from which both experimental procedure and theory may proceed 

 simultaneously to provide more concrete and reliable data and concepts 

 than are now possible. The presentation in this chapter is always approxi- 

 mate, usually crude, and often naive. It is hoped that it will contain some 

 stimulation for a quantitative approach to intermolecular interactions in 

 biological systems and assist in the evolution of exciting and fruitful coop- 

 eration between the physical and biological disciplines. If this is accom- 

 plished, the inadequacies of the present treatment may be forgiven. Con- 



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