Abstract
Covariation between sites can arise due to a common evolutionary history. At the same time, structure and function of proteins play significant role in evolvability of different sites that are not directly connected with the common ancestry. The nature of forces which cause residues to coevolve is still not thoroughly understood, it is especially not clear how coevolutionary processes are related to functional diversification within protein families. We analyzed both functional and structural factors that might cause covariation of specificity determinants and showed that they more often participate in coevolutionary relationships with each other and other sites compared with functional sites and those sites that are not under strong functional constraints. We also found that protein sites with higher number of coevolutionary connections with other sites have a tendency to evolve slower. Our results indicate that in some cases coevolutionary connections exist between specificity sites that are located far away in space but are under similar functional constraints. Such correlated changes and compensations can be realized through the stepwise coevolutionary processes which in turn can shed light on the mechanisms of functional diversification.