Aromatic interactions in β-hairpin scaffold stability: A historical perspective

A systematic analysis of the beta hairpin motif in the Protein Data Bank

“…Fig. 2) as aromatic residues are known to stabilize beta hairpin structures 18,19 . Lastly, appropriate contacts between hairpin beta strands are imperative to provide structural stability.…”

“…Efforts to design such structures have benefited from several decades of research aimed at identifying how beta hairpins form [15][16][17] and what factors influence their stability and specific activity. 2,[18][19][20][21] Examples of synthetic proteins that have successfully adapted the beta hairpin motif for specialized functions include hydrogels, 9 antimicrobial peptides, 22 and various molecules with material science applications. 8 Although largely successful, beta hairpin engineering efforts are typically limited to testing relatively small libraries involving derivatives of a stable scaffold structure or existing protein via peptidomimetics.…”

“…8 Although largely successful, beta hairpin engineering efforts are typically limited to testing relatively small libraries involving derivatives of a stable scaffold structure or existing protein via peptidomimetics. 2,4,19,23,24 With the increasing availability of high throughput screening platforms to test for activity in large libraries of de novo sequences [25][26][27] there is an obvious need for broader 4 design principles that can be applied to the generation of libraries with millions of diverse beta hairpin containing proteins. Knowledge of amino acid propensities throughout known beta hairpin sub-structures could inform such design principles but existing catalogs are too broadly focused on beta sheets, outdated, or limited in scope.…”

The unusual conformation of cross‐strand disulfide bonds is critical to the stability of β‐hairpin peptides

“…A selection of these peptides is shown in Figure 2A. In addition to their potential as pharmaceuticals, β-hairpin peptides have been studied extensively as models for protein folding and templates for protein engineering [39][40][41][42][43][44][45]. Most studies have focused on understanding the contribution of specific sequences and residues, as well as the presence and position of disulfide bonds, to the structural stability of these peptides.…”

A systematic analysis of the beta hairpin motif in the Protein Data Bank

“…In addition to its prevalence in nature, the beta hairpin motif is stable in even small structures and extensively adaptable to specific functions, making it a popular choice in engineered protein structures. Efforts to design such structures have benefited from several decades of research aimed at identifying how beta hairpins form 15–17 and what factors influence their stability and specific activity 2,18–21 . Examples of synthetic proteins that have successfully adapted the beta hairpin motif for specialized functions include hydrogels, 9 antimicrobial peptides, 22 and various molecules with material science applications 8 …”