Towards descriptor of elementary functions for protein design

We review studies of the protein evolution that help to formulate rules for protein design. Acknowledging the fundamental importance of Dayhoff's provision on the emergence of functional proteins from short peptides, we discuss multiple evidences of the omnipresent partitioning of protein globules into structural/functional units, using which greatly facilitates the engineering and design efforts. Closed loops and elementary functional loops, which are descendants of ancient ring-like peptides that formed fist protein domains in agreement with Dayhoff's hypothesis, can be considered as basic units of protein structure and function. We argue that future developments in protein design approaches should consider descriptors of the elementary functions, which will help to complement designed scaffolds with functional signatures and flexibility necessary for their functions.