[3][4] Families are sometimes grouped together into larger clades called superfamilies based on structural similarity, even if there is no identifiable sequence homology.
[2][10] Subfamilies can be defined within families to denote closely related proteins that have similar or identical functions.
Due to evolutionary shuffling, different domains in a protein have evolved independently.
A protein–protein binding interface may consist of a large surface with constraints on the hydrophobicity or polarity of the amino-acid residues.
Certain gene/protein families, especially in eukaryotes, undergo extreme expansions and contractions in the course of evolution, sometimes in concert with whole genome duplications.
[15] This expansion and contraction of protein families is one of the salient features of genome evolution, but its importance and ramifications are currently unclear.
[16] The algorithmic means for establishing protein families on a large scale are based on a notion of similarity.