The contribution of pairwise amino-acid interactions to the stability of collagen triple heliceshas remained elusive. Progress in this area is critical for the prediction of triple helical stabilityfrom sequences and the preparation of mimetic materials based on this fold. Here we reporta sequence-based scoring function for triple helices that takes into account the stabilityconferred to collagen by axial lysine–aspartate salt bridges. This function is used to predictthe stability of a specific register formed from three distinct peptide sequences and that of allalternative compositions and registers. In the context of a genetic algorithm we use it to selectsequences likely to self-assemble with high stability and to the exclusion of the other 26 possiblecombinations. We validate our methodology by synthesis and structural characterization of thedesigned peptides, which self-assemble into a highly stable ABC triple helix with control overboth composition and register.
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