Adaptability and specificity: how do proteins balance opposing needs to achieve function?

Many proteins select from a small repertoire of 3-dimensional folds retained over evolutional timescales and recruited for different functions, with changes in local structure and sequence to enable specificity. Recent studies have revealed the evolutionary constraints on protein dynamics to achieve function. The significance of protein dynamics in simultaneously satisfying conformational flexibility/malleability and stability/precision requirements becomes clear upon dissecting the spectrum of equilibrium motions accessible to fold families. Accessibility to highly conserved global modes of motions shared by family members, to low-to-intermediate-frequency modes that distinguish subfamilies and confer specificity, and to conserved high-frequency modes ensuring chemical precision and core stability underlies functional specialization while exploiting highly versatile folds. These design principles are illustrated for the family of PDZ domains.