Creating new building blocks for synthetic biology

Figure 1: Design principal, biophysical characterization, and structures. Helical wheel, Circular dichroism, and structure of (i) trimer coiled coil (PDB ID: 7qdk) of the starting sequence with heptad repeat and (ii) left-handed 310- helical assembly (PDB ID: 7qdi)

Over the decades biologists have been tweaking existing proteins to make them work better, or not at all, to assist and improve human health. Recently, scientists have been turning their attention to protein engineering – designing novel proteins to perform specific functions.

Using chemical synthesis, a team of scientists from the University of Bristol have designed a completely new molecule using a rare form of the alpha helix protein building block called the 3-10 helix. This was achieved by combining amino acids—the chemical units of proteins—that are found in natural proteins with others that are not

X-ray confirmation

The team used Diamond’s X-rays to confirm their solution studies. Studying the crystallised form of the protein enabled them to see that the designer proteins formed bundles of pure 3-10 helices that could essentially act like a scaffold. This was a never-seen-before molecule.

Figure 2: Crystal structure of de novo designed 310-helix assembly. Backbone ribbon structures coloured blue to red from the N to C termini for: (i) orthogonal views D-310HD (PDB ID: 7qdi). (ii) Side chain of D-Leu residues is shown in space-filling representation to highlight the intimate packing to form a consolidated hydrophobic core. (iii) Packing of D-Glu (magenta) and D-Lys (blue) residues, plus Aib (green) residues in space-filling representations.

The creation of a novel, molecular scaffold opens up a range of possibilities with regards to designing proteins with a purpose. The Bristol team will now look to probe this so-called "dark matter" of protein structure to explore chemistries and functions that go beyond those of natural proteins.