De Novo Proteins

Proteins are an essential part of any organism. They allow each cell to do what they are meant to do, they build and repair tissues (muscles, skin, bones, hair), transport oxygen in the blood, regulate hormones, support immunity, and drive chemical reactions in the form of enzymes. Proteins are formed in cells when RNA is translated into amino acids, which fold into shapes that give a protein its function. These proteins are made naturally within cells using the DNA and RNA from those cells. De novo proteins come from making synthetic proteins rather than from cells naturally.

De novo proteins arise from previously non-coding DNA rather than from modifications of existing genes. Compared to random synthetic proteins, many de novo proteins show stability and solubility. This suggests functional proteins arise more easily than previously thought, lending to increase our understanding of the origins of life itself and how evolution may generate new biological functions over time. Additionally, de novo proteins may originate from random amino acid sequences through evolution and laboratory selection. Random polypeptides can sometimes fold into stable structures, and through mutation and selection, they can develop useful biological functions.

Because de novo proteins are designed by humans, scientists can choose their structure and amino acid composition to achieve specific functions. One increasingly important tool for this process is artificial intelligence (AI). AI and computational methods in general are being used widely in de novo protein design to replicate molecular conditions and protein folding. Instead of modifying natural proteins, scientists can design entirely new shapes and functions for proteins with different applications in medicine, biotechnology and synthetic biology, including drug development and targeted therapies.

The creation of a de novo protein begins with choosing a desired function. This function could be binding a virus, carrying a molecule or catalyzing a reaction. Scientists then design an amino acid sequence, often with the help of AI. Next, a DNA sequence encoding the protein is chemically synthesized. The DNA is then inserted into cells, where it is transcribed and translated into the desired protein.

References:

B;, Tong CL;Lee KH;Seelig. “De Novo Proteins from Random Sequences through in Vitro Evolution.” Current Opinion in Structural Biology, U.S. National Library of Medicine, pubmed.ncbi.nlm.nih.gov/33517151/. Accessed 26 May 2026.

Kortemme, Tanja. “De Novo Protein Design-from New Structures to Programmable Functions.” Cell, U.S. National Library of Medicine, 1 Feb. 2024, pmc.ncbi.nlm.nih.gov/articles/PMC10990048/.

Heames, Brennen, et al. “Experimental Characterization of de Novo Proteins and Their Unevolved Random-Sequence Counterparts.” Nature News, Nature Publishing Group, 6 Apr. 2023, www.nature.com/articles/s41559-023-02010-2.

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