Summary of strategies examined for peptide backbone modification in β-sheets. The most effective sheet modifications examined lead to native-like tertiary folding behavior with thermodynamic fold stability comparable to the prototype protein on which the modified backbones are based. Here, we report the side-by-side comparison of several different strategies for peptide backbone modification in β-sheet secondary structures with the goal of identifying the best method for replacing a multi-stranded sheet in a protein tertiary fold. As an example, when incorporated in each strand of a hairpin-forming peptide, appropriately substituted β-amino acid residues (homologated analogues of α-residues) can maintain native-like folding, 6a,6b but the same modifications abolish folding entirely when made in a four-stranded β-sheet in a small protein. Unfortunately, the lessons learned in the hairpin context are not always applicable in a more complex protein tertiary fold. 6 Hairpin model systems, widely used in fundamental studies on β-sheet formation in proteins, 9 have proved valuable in assessing sheet propensity of unnatural building blocks. Building on pioneering work carried out largely in organic solvents, 8 we have recently focused on developing strategies for the design of heterogeneous-backbone β-sheet mimics that fold in water. 7 A fundamental question that must be addressed for sequence-guided backbone alteration to be effective for the widest array of target folds is how to best apply chemical modification without disrupting sequence-encoded folding.Īmong common protein secondary structures, sheet folds have proved more challenging targets than helices or turns for mimicry by unnatural oligomers. The versatility of the above method for mimicry of isolated α-helix 5 and β-sheet 6 secondary structures has recently been leveraged to simultaneously modify all the secondary structures in a small protein tertiary fold. 4 Bridging the gap between these observations and precedent on de novo foldamer design 2 suggests an approach toward protein mimicry, in which a number of α-residues in a sequence with known folding behavior are replaced with various unnatural building blocks to generate heterogeneous backbones capable of adopting native-like folds. Folded proteins can tolerate diverse backbone modifications without compromising sequence-encoded folding. One design concept that shows promise in addressing the challenge of tertiary structure mimicry is the systematic backbone alteration of natural sequences. Reproducing a wider selection of natural protein structural motifs with unnatural oligomers is an important goal because it opens the door to reproducing the full repertoire of functions enabled by those folds. Although significant progress has been made with helix-turn-helix targets, 3 these represent only a small fraction of the diverse array of folds found in nature. In more than two decades of work showing increasingly sophisticated structures from unnatural backbones, tertiary folds like those commonly found in proteins have proven difficult to recreate. Synthetic oligomers with the capacity to adopt discrete folded structures (“foldamers”) 1 have received significant research attention, 2 due in part to their ability to mimic natural peptide folding patterns.
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