First such advance makes possible creation of new beta-barrel proteins to precisely target small molecules. For the first time, scientists have created, entirely from scratch,  a protein capable of binding to a small target molecule. The study was published in the journal Nature.

Binding Proteins

Previously, such small-molecule binding proteins have been made by altering proteins already existing in nature. That approach  significantly limited the possibilities. The ability to make such proteins from scratch, or “de novo,” opens the way for scientists to create proteins unlike any found in nature. 

These proteins can be custom-designed with high precision and bind to and act on specific small molecule targets. The technique should have wide application in research, medicine, and industry.

To make the protein, the researchers had to achieve another first: Creating from scratch a cylinder-shaped protein called a beta-barrel. The beta-barrel structure was ideal because one end of the cylinder could be designed to stabilize the protein, while the other end could be used to create a cavity that can serve as the binding site for the target molecule.

Amino Acids

Proteins are made of long chains of amino acids. Once synthesized, these chains fold into precise shapes that allow the proteins to perform their functions. The shapes these chains assume are typically incredibly convoluted, but two regular features often occur alpha-helices, which form when the sections chain winds around a central axis, and sheet-like structures, called beta-sheets.

Beta-sheets form when two or more sections from different parts of the amino acid chain, because of folding, run side-by-side in 3-D space. These sections are “stitched together” by hydrogen bonds, creating a sheet-like structure. These beta-sheets, in turn, can assemble into barrel-like structures, called beta-barrels. In nature, beta-barrels proteins bind a wide range of small molecules.

To design the new protein, Dou and Vorobieva used A software platform, developed in the Baker lab, called Rosetta. It can predict what shape a particular chain of amino acids will assume after synthesis and can tell how changing individual amino acids along the chain may alter that shape.

Protein Structures

RIF rapidly identifies all potential structures of cavities that fulfill the pre-requisites for binding specific molecules. Equipped with the new RIF docking methods, Dou, Vorobieva, and Sheffler designed the beta-barrels to bind a compound called DFHBI, a component similar to what is housed inside the green fluorescent protein, which fluoresces when exposed to certain frequencies of light.

Fluorescent Protein

Green fluorescent protein is routinely used in biological research to locate molecules and structures within a living organism and to track their movement.

An effectively unlimited set of backbone structures with shapes customized to bind the molecule of interest.” Equally important,” he added, “it greatly advances our understanding of the determinants of protein folding and binding beyond what we have learned from describing existing protein structures.