ABSTRACT
Bottom-up approaches to protein design rely on a rational understanding of the fundamental principles that govern protein structure and stability. Such rationalbased approaches contrast with methods that rely on random sequence libraries. While random libraries enable the exploration of vast amounts of sequence space, most members of randomly constructed libraries do not fold into stable proteinlike structures (Mandecki 1990; Davidson et al. 1995). The goal of bottom-up rational design is to direct the formation of a desired three-dimensional structure by using knowledge-based approaches to design favorable interactions (both local secondary structures and long-range tertiary interactions) into the design of a linear amino-acid sequence.
