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  • Writer's pictureVedant Parikh

Lab Notes on: Nanosandwiches

Updated: Aug 11, 2023

Rebecca Zhang's notes on a unique molecular sandwich.


A typical sandwich consists of two slices of bread with some sort of filling between them. Peanut butter, chicken, ham, or tomatoes are just some of the things that a sandwich could contain. However, a nanosandwich consisting of proteins and nucleic acids is slightly different. The researchers of the paper “Nano-sandwich composite by kinetic trapping assembly from protein and nucleic acid” described their self-assembling nanosandwich as consisting of a DNA and RNA “bread” with a protein core “filling” called streptavidin, all held together using biotin ligands that can bind to the protein.

In biology, ligands are molecules that bind to another larger molecule, more specifically a protein. Ligands also exist in chemistry, where they are defined as ions or molecules that bind to a metal atom. Biotin is an essential form of vitamin B that helps convert the carbohydrates, fats, and proteins one consumes into energy.

Nucleic acids and proteins have long been used in the formation of biomaterials and recognized as potential parts of a self-assembling composite. This is possible since proteins can fold in various 3D manners and nucleic acids have the quality of complementary base pairing.

Proteins can exist in various structures: 
 1. Primary structure - the protein is just a chain of amino acids 
 2. Secondary structure - the chain of amino acids takes on the               
   “texture” of either helices or pleats
 3. Tertiary structure - the textured chain of amino acids folds into a 
   3D shape
 4. Quaternary structure - the 3D chain of amino acids joins with other
   proteins to form a more complex structure

DNA and RNA, the nucleic acids, are strings of base pairs that code for specific proteins. These proteins are made using the RNA base pairs, which are derived from the DNA base pairs. There are four different base pairs, and of these four, two base pairs bind to each other and the other two bind to each other. DNA has two strings of base pairs that are complementary, meaning that when the strings are lined up, each base pair on one string can bind to the opposite base pair on the other string.

Prior to this study, complexes had been made by placing proteins on a DNA scaffold, placing proteins on an RNA scaffold, or by combining DNA and RNA, but never before had a complex capable of self-assembly consisting of DNA, RNA, and protein been made. The researchers used RNA corner modules and DNA connector modules to form nanotriangles for the outside, the protein streptavidin to create the core, and biotin ligands to keep the nanosandwich together. In the nanotriangles, the RNA corner modules were the bulk of the structure. A guide DNA (also called DNAin since it was on the inside of the triangles) with three hybridization sites allowed for the formation of the triangles and DNA connectors (also called DNAout since they were on the outside of the triangles) acted as carriers for biotin-conjugated oligonucleotides. In the study, the researchers experimented with zero, one, two, or three biotin ligands.

Oligonucleotides are short sequences of DNA or RNA that have many possible applications. Biotin-conjugated oligonucleotides are simply oligonucleotides with biotin bound to them.

The first attempt at constructing the nanosandwich mostly ended with the structures simply aggregating, or clustering. This method involved mixing streptavidin with already prepared nanotriangles. Only nanotriangles with just one biotin ligand succeeded in forming the desired sandwich, with the sandwiches having one, two, or three triangles bound to the protein core. The triangles with two and three ligands likely failed due to the kinetic and chemical relationship of the biotin and streptavidin, where a quick binding of the first ligand inhibited the binding of the subsequent ligands.

To solve this issue, instead of preparing the nanotriangles in advance, the researchers harnessed the quickly assembling quality of the DNA-RNA triangles to prevent aggregation. In this new method, biotin-conjugated oligonucleotides were bound to streptavidin to form a protein-DNA precursor for the core, which was then mixed with guide DNAin and DNAout connectors. The RNA corner modules were added last to the mixture, which catalyzed the rapid assembly of the nanotriangles and subsequently sandwiched the protein cores connected to the biotin between the triangles. The resulting nanosandwich incorporates the qualities of all its parts: the protein core functioning as a center, the RNA serving as building blocks and as a catalyst for self-assembly, and the DNA acting as connectors.

With the success of this study, these nanosandwich composites have a wide variety of potential uses. For example, a broader application is that they can be used in sequences for more complex biomaterials. They can also be used to learn more about the molecular structures that occur in human bodies. Though they have not yet been thoroughly tested for in vivo use, or use in the body, the nanosandwiches can still be applied in vitro to further the nanotechnology field and the knowledge we have of biology as a whole.

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