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

Abstract

The beta hairpin motif is a ubiquitous protein structural motif that can be found in molecules across the tree of life. This motif, which is also popular in synthetically designed proteins and peptides, is known for its stability and adaptability to broad functions. Here we systematically probe all 49,000 unique beta hairpin substructures contained within the Protein Data Bank (PDB) to uncover key characteristics correlated with stable beta hairpin structure, including amino acid biases and enriched inter-strand contacts. We also establish a set of broad design principles that can be applied to the generation of libraries encoding proteins or peptides containing beta hairpin structures.

Predicting pathogenicity for novel hearing loss mutations based on genetic and protein structure approaches

“…The p.Thr629Met mutation in the patient lies in the beta hairpin of LeuRS between strands I-I of the LS domains and leads to the disruption of the motif and protein stability. This is in accordance with the observation that beta hairpin motifs are implicated in protein stability 29 , 30 . Moreover, the substitution of p.Ala508 in Escherichia coli LeuRS (analogous to human LeuRS p.Thr629) with a nonpolar methionine disrupts the structure and/or position of the leucine-specific domain and thus shifts the location of the KMSKS loop and reduces the catalytic efficiency 16 , 31 .…”

Designing and identifying β-hairpin peptide macrocycles with antibiotic potential

“…Our design scheme leveraged our recently completed systematic analysis of more than 49,000 β-hairpin motifs in the Protein Data Bank. This analysis identified position-specific amino acid preferences in the strand and turn regions ( 14 ). Using this information, we designed two ribosomally encoded 20–amino acid cyclic β-hairpin peptide libraries (Fig.…”

“…These two libraries were intentionally designed to facilitate the development of stable antiparallel β strands with amphipathic faces generated via the periodic alternation of aliphatic and charged/polar residues. We identified and applied a preference for glycine, asparagine, and aspartic acid in or near the turn regions (14)(15)(16) and excluded proline in contrast to canonical β-turn design (17)(18)(19)(20). We also excluded aromatic residues because they promote mammalian toxicity despite their positive effects on β-hairpin structure (21).…”

Designing β-hairpin peptide macrocycles for antibiotic potential

“…Our design scheme leveraged our recently completed systematic analysis of over 49,000 β-hairpin motifs in the Protein Data Bank. This analysis identified position specific amino acid preferences in the strand and turn regions ( 15 ). Using this information, we designed two ribosomally encoded twenty amino acid cyclic β-hairpin peptide libraries ( Fig.…”

“…These libraries were intentionally designed to facilitate the development of stable antiparallel β-strands with amphipathic faces generated via the periodic alternation of aliphatic and charged/polar residues. We identified and applied a preference for glycine, asparagine, and aspartic acid in or near the turn regions (15)(16)(17) and excluded proline in contrast to canonical βturn design (18)(19)(20)(21). We also excluded aromatic residues because they promote mammalian toxicity despite their positive effects on β-hairpin structure (22).…”