New strategies in protein design.

Initially, it was hoped that very simple rules could be sued to design proteins that embody all the characteristics of natural proteins. Indeed, with single-domain proteins as targets, it has been possible to design proteins that adopt the desired global fold. Yet, designed proteins with well defined structures and properties that mimic those of natural proteins remain elusive. Recent efforts in protein design have been directed toward addressing the basis for non-native characteristics in most protein designs. Although it is clear that specific tertiary interactions between all residues in a protein contribute to the final folded state, much attention has been placed on optimizing the packing of side chains in the hydrophobic core, with substantial success.