α-Helical Scaffolds Protein Design

Protein structures are mostly built from secondary structural elements, including α-helices, β-sheets, and canonical turns, with well-understood and predictable patterns of backbone torsion angles and hydrogen bonds. As a skillful expert with expertise in synthetic protein design, Creative Biolabs takes efforts to define the rules for the α-helix formation and create other elements to constitute protein structure. Our strategy is based on the assembly of protein structures from peptide fragments, as well as high-resolution sampling approaches and all-atom energy functions to produce a variety of new, idealized protein folds.

Distribution of residues on a canonical α-helix. Fig.1 Distribution of residues on a canonical α-helix. (Jayatunga, 2014)

The α-helix is the most common element of protein secondary structure, with approximately 30% of residues in this structure. It’s a key fragment of natural proteins that consists of a peptide chain coiled into a right-handed spiral conformation and settled by hydrogen bonds between the CO and NH groups in the backbone. Naturally-occurring single α-helices, are rich in Arg, Glu, and Lys residues, and stabilized by numerous salt bridges. An α-helix is defined by a tight helical turn (3.4 residues per turn), thus forming three distinct binding surfaces, with the i, i+4, and i+7, residues arrayed on the same face. Of the protein-protein interactions found in the Protein Data Bank (PDB), 62% have an α-helix at the interface, elucidating the importance of this element in protein’s recognition. They’re also present in more complex recognition domains, such as membrane-bound proteins and DNA binding motifs.

Peptide design. Fig.2 Peptide design.

In natural proteins, α-helices are the most abundant secondary structural elements creating vital parts of the large, characterless interfacial regions of many therapeutically-relevant protein interactions. The rational design of helix mimetics is an appealing small-molecule strategy, but the first generation of scaffolds showed a relatively small number of residues on a single recognition surface. At Creative Biolabs, we help clients to engineer proteins with various existing scaffolds, taking into consideration factors for proper folding and stability. The synthesis and structural determination of engineered proteins are available, whose specific features can be further assessed by sophisticated biochemical and biophysical techniques.

Nowadays, we have an excellent understanding of the principles for α-helix formation due to experimental studies of helices in isolated peptides and proteins, an examination of helices in crystal structures, together with computer modeling and simulations. Here, there is a list of structural properties that are important for designing peptide helices, including:

  • 3D crystal structure of the α-helix
  • Amino acid preferences (e.g. terminal or interior position)
  • Noncovalent side-chain interactions
  • Examining the design
  • The helix dipole
  • Phosphorylation
  • Disulfide bonds
  • H-bonding formation
  • Metal binding
  • Helix templates

Recently, there have been great advances in the area of computational protein design. At Creative Biolabs, our scientists divide the process of computational design into two coupled problems. The first one is to select or generate a backbone scaffold that is designable. The second one is to find needed sequences that are able to fold into the desired backbone structure. The protocols we introduce for the de novo design of highly stable α-helixes using optimal algorithms.

The design of synthetic protein that folds into prescribed structures is challenging. General solutions to this require geometric descriptions of protein folds and strategies to fit sequences to these. The α-helical scaffolds represent a promising class of protein for that and offer considerable scope to explore hitherto unseen structures. As a top-ranking partner in the world, Creative Biolabs provides customers one-stop design and engineering services for synthetic binding proteins using α-helical scaffolds and other elements. Our experts combine geometrical subjects, knowledge-based scoring, and atomistic modeling to facilitate the design of novel channel-containing α-helical barrels. If you’re interested in any services, please don’t hesitate to contact us or send us an inquiry.


  1. Jayatunga, M.K.; et al. α-Helix mimetics: outwards and upwards. Bioorg Med Chem Lett. 2014, 24(3): 717-724.

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