Coiled Coil - Coiled-coil Design

Coiled-coil Design

The general problem of deciding on the folded structure of a protein when given the amino acid sequence (the so-called protein folding problem) has not been solved. However, the coiled coil is one of a relatively small number of folding motifs for which the relationships between the sequence and the final folded structure are comparatively well-understood. Harbury et al.. performed a landmark study using an archetypal coiled coil, GCN4, in which rules were established that govern the way that peptide sequence affects the oligomeric state (that is, the number of alpha-helices in the final assembly). The GCN4 coiled coil is a 31-amino-acid (which equates to just over four heptads) parallel, dimeric (i.e., consisting of two alpha-helices) coiled coil and has a repeated isoleucine (or I, in single-letter code) and leucine (L) at the a and d positions, respectively, and forms a dimeric coiled coil. When the amino acids in the a and d positions were changed from I at a and L at d to L at a and I at d, a trimeric (three alpha-helices) coiled coil was formed. Furthermore, mutating the a and d positions both to L resulted in the formation of a tetrameric (four alpha-helices) coiled coil. These represent a set of rules for the determination of coiled coil oligomeric states and allows scientists to effectively "dial-in" the oligomerization behavior. Another aspect of coiled coil assembly that is relatively well understood, at least in the case of dimeric coiled coils, is that placing a polar residue (in particular asparagine, N) at opposing a positions forces parallel assembly of the coiled coil. This effect is due to a self-complementary hydrogen bonding between these residues, which would go unsatisfied if an N was paired with, for instance, an L on the opposing helix.