  We are interested in the subtle variations of function among the members of a
protein family. A protein family is usually subdivided into subfamilies based
on functional differences. Existence of this functional diversity is essential
for the successful performance of physiological roles expected of the family.
This presents a unique problem: there must be preservation of the active site;
simultaneously there should be specificity of protein action according to
subfamily. Though the classification into subfamilies is by no means a
formalized one, it is most times based on the character of regulation of the
primary function. The function of a subfamily is a modification of when the
protein performs its function, for example, by changing the protein's
sensitivity to regulatory factors. Rarely, a subfamily possesses a function
completely different for its family. A study of these details is necessary for
understanding the fine-tuning of protein function. I describe a theory for
studying subfamily-based functional specificity and then validate it with an
example application to deciphering the residue-level basis of fine functional
variations in the diverse set of K+-channel subfamilies. I provide specific
results that will be useful to channel physiologists, whereas the strategy
developed will be widely applicable to problems in comparative and functional
genomics.
