Off-atom charge sites

The PPD and shell models are nearly equivalent in this sense, because they model the electrostatic potential via static point charges and polarizable dipoles (of either zero or very small extent). Accuracy can be improved by extending the expansion to include polarizable quadrupoles or higher order terms.The added computational expense and difficulty in parameterizing these higher order methods has prevented them from being used widely. The accuracy of the ESP for dipole-based methods can also be improved by adding off-atom dipolar sites. 

Fig. 8.15. Liver alcohol dehydrogenase catalyzes the oxidation of ethanol (shown in blue) to acetaldehyde. The active site of liver alcohol dehydrogenase contains a bound zinc atom, and a serine side chain -OH and a histidine nitrogen that participate in the reaction. The histidine pulls an off the active site serine, which pulls the off of the substrate -OH group, leaving the oxygen with a negative charge that is stabilized by zinc.

Experimental pKa data suggest that cyano substitution can exert substantial long-range effects on phenol acidity, but the reason for these effects is not obvious. If ion-dipole interactions were to blame, the effect would fall off with increasing ion (0 ) - dipole (CN) separation. If electron delocalization were responsible, then the effect would be accompanied by charge transfer between the ionic site (O) and other atoms in the molecule. 

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