The Binary Code Strategy For Protein Design

The binary code strategy is based on the design of specific patterns of polar and nonpolar amino acids in the primary sequence. The strategy is described as binary because the amino acids are treated as belonging to one of two groups: polar or nonpolar. This polar/nonpolar patterning is designed to match the inherent structural periodicity of the desired secondary structure (a-helix or ^-strand), and thereby specify amphiphilic units of secondary structure (Figure 11.3). When these amphiphilic secondary structures fold into the target tertiary structure, their nonpolar faces become buried against one another. Once folded, the entire sequence partitions its side chains such that hydrophobic amino acids are sequestered into the core and hydrophilic amino acids are exposed on the exterior of the protein.

The binary code strategy incorporates both rational and combinatorial features. Thus, the positions of polar and nonpolar residues are designed explicitly; however, the exact side-chain identities at each position are allowed to vary combinatorially. The combinatorial mixtures of polar or nonpolar amino acids are specified by degenerate codons (Figure 11.4) in combinatorial libraries of synthetic genes.

The binary code strategy focuses the exploration of sequence space into those regions that favor folded structures. By carefully designing template structures, it is possible to design libraries with a range of tertiary folds. In principle, all-alpha, all-beta, and combined alpha/beta structures are suitable design targets, although

Protein Binary Code

FIGURE 11.3 (see color insert following page 178) Binary pattern strategy applied to (A) an a-helix and (B) a ^-strand. Nonpolar residues are represented by yellow circles and polar residues are represented by red circles. In the a-helix design, nonpolar residues are placed every three to four positions, while in the ^-strand design a nonpolar residue is placed at every other position. In each figure, a head-on view is shown on the left and a side view on the right.

FIGURE 11.3 (see color insert following page 178) Binary pattern strategy applied to (A) an a-helix and (B) a ^-strand. Nonpolar residues are represented by yellow circles and polar residues are represented by red circles. In the a-helix design, nonpolar residues are placed every three to four positions, while in the ^-strand design a nonpolar residue is placed at every other position. In each figure, a head-on view is shown on the left and a side view on the right.

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