The molecule that folds by itself

Title: Complex Molecules That Fold Like Proteins Can Emerge Spontaneously

Author: Bin Liu, Charalampos G. Pappas, Ennio Zangrando, Nicola Demitri, Piotr J. Chmielewski, and Sijbren Otto

Journal: J. Am. Chem. Soc., 2019, 141 (4), pp 1685–1689

DOI: 10.1021/jacs.8b11698

Folding a paper maybe easy, but folding a molecule is much more complicated. Yet, this sophisticated process is happening in our body every single moment! For instance, proteins in our body fold and re-fold themselves in order to absorb essential nutrients to our cells. Scientists call these and other folding molecules “foldamers” and many have been developing and synthesizing new foldamers that can perform complex functions.

Careful design and synthesis are necessary for foldamer development. To simplify the process, current design often makes use of nearby interactions between simple, neighboring units in the foldamers. However, creating foldamers that involve interactions between far away units is often found to be difficult, but these long-range interactions are commonly found in nature. Thus, new methods need to be developed to get human design closer to what’s possible in the natural world.

In view of the current challenge, researchers have proposed an approach called dynamic combinatorial chemistry (DCL). This is a method that generates new molecules through reversible reaction of simple building blocks. The building blocks are in thermal equilibrium until they come into contact with other molecules that can exchange building blocks with them. The process continues until a molecule folds up itself. The folded molecule is more stable and unable to engage in further exchanging interactions and therefore exists as the final product.

In this study, researchers first studied nature’s folded macromolecules and selected two types of subunits to maximize the chances of accessing foldamers in their DCL. They have developed a building block 1 (Figure 1) that contains two subunits based on the key structural elements in proteins and nucleic acids, which are the essential molecules in our body. By having both subunits on a single building block, they aimed to produce fundamentally new foldamers.


Figure 1 Molecule 1 is the building block containing the two subunits from proteins and nucleic acids. When exposed to oxygen, the building block could give rise to molecules of different lengths. At a higher concentration of the building block, a large molecule (15mer) containing 15 subunits is formed.

The building block contains two thiol (SH) groups, which will be oxidized, when exposed to oxygen, into disulfide bonds that join multiple building blocks.  In the absence of noncovalent interactions, the building blocks would give rise to small molecules. Yet, at a higher concentration of the building block, unusually large molecule result. Researchers have found the product contains as many as 15 subunits of the building blocks (15mer)! By modifying different solvent compositions or by addition of salts, they have proposed that hydrophobic interactions are important in stabilizing the product compound. Through various chemical characterization techniques including X-ray crystallography, they have proven that the product compound has a folded structure.

The story of foldamers discovery does not end upon the success of its formation. Researchers have further studied its folding process. They investigated the molecule through a  technique called circular dichroism spectroscopy. Through adjusting various solvents and temperatures, they finally unfolded the 15mer using DMF solution at an elevated temperature. They demonstrated the heating and cooling the DMF solution could give reversible signals of the CD spectroscopy which come from folding and unfolding the 15mer.

In short, scientists have identified new foldamers and managed to produce molecules of precisely defined length with high product yield and less synthetic effort. They have therefore proposed such an approach as an efficient way to develop new foldamers. In addition, they have proven these complex foldamers could selectively and spontaneously result from a mixture of interconverting molecules. Since foldamers play a significant role in our body, these structures could also give us new insight into the origin of life!

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