DEPENDENCE OF INTERACTION ENERGY UPON FIT 301 



DEPENDENCE OF INTERACTION ENERGY UPON FIT 



It would be superfluous to emphasize further the importance of proper 

 fit for the binding of many substances to proteins after what has been pre- 

 sented already in this chapter, but certain aspects of this problem may be 

 summarized at this time. In discussing the fit of a molecule to a protein 

 surface it is well to remember that one must sometimes take into account 

 the contour of the molecules with water of hydration included, since un- 

 doubtedly interactions occur where the water is not displaced. 



Generally speaking there are three different, but closely related, types 

 of fit. (1) Most inhibitor molecules possess two or more attachment points 

 by which they are bound to the enzyme, the binding energy and hence the 

 inhibition depending upon the degree to which these attachment points 

 correspond to appropriate groups on the enzyme. Thus molecules of the type: 



Rj — X — Rj Rj — X\ 



Rj 



for which the attachment points are represented by R and the remainder 

 of the molecules determining the spatial relations of these points by X, 

 would be bound maximally to enzymes only if these R-groups can all come 

 into intimate contact with enzyme groups with which they have affinity. 

 The actual distances between these R-groups and the flexibility of the mole- 

 cules will be the major factors in determining the efficacy of the inhibitor 

 and there are many examples where alteration of the distance by addition 

 or subtraction of intervening units causes marked changes in inhibitory 

 potency. (2) In certain instances there would seem to be no dominant at- 

 tachment points in the bound molecule and the over-all interaction energy 

 is dependent upon the more or less continuous fit of the molecule to the 

 protein surface, adequate binding arising from the summation of many 

 small van der Waals' type forces. Such would be the case in the binding 

 of steroids to proteins. Here the most important factor is the total surface 

 contour with respect to regions on the protein that are spatially comple- 

 mentary to the bound molecule. The introduction, for example, of even 

 a small group on the side of the molecule which interacts with the protein 

 may reduce the fit sufficiently to inhibit binding. (3) Finally there are the 

 situations where fit within an invagination of the protein surface occurs 

 and these cases perhaps present the most stringent requirements for fit. 

 An energy-distance curve, such as is shown in Fig. 6-19 for a methyl 

 group within a protein cavity, demonstrates what will happen as either 

 the group or the cavity alters in size. In such cases, there is an optimal 

 size for both group and cavity, deviations from which will result in a 

 lessening of the interaction energy. 

 It would be convenient if the requirement for fit in any particular in- 



