Scientists discover a wide variety of protein folds that have not been explored in nature


July 12, 2023

(Nanowerk News) A groundbreaking study has shed new light on the astonishing diversity of protein structures and their folding in nature. The researchers set out to reveal the extent to which nature has explored the vast landscape of protein topological possibilities. The results have uncovered yet unexplored sequences of protein folding, expanding our understanding and uncovering the depths of the protein universe.

This research has been published in the journal Natural Structural and Molecular Biology (“Exploration of novel αβ-protein folds via de novo design”).

Proteins, the building blocks of life, fold into specific three-dimensional structures, allowing them to carry out their biological functions. The three-dimensional structure of a protein is determined by its amino acid sequence. While experimental techniques have succeeded in unraveling the structure of many proteins over the years, the discovery of new protein folds, which are determined by the arrangement and connectivity of the α helices and β strands, is becoming increasingly rare. This begs the question: how extensive is the unfolding space of proteins that has not been explored by nature? In an attempt to answer this old question, theoretical studies have been carried out; However, experimental validation is lacking.

To answer this question, the research team embarked on a study that combined theoretical predictions for novel protein folding with experimental validation of their de novo design. Newly designed folding protein Newly designed folding protein. From above, protein names, topology diagrams (circles represent α helices, triangles and arrows represent β strands), computationally designed structures, and experimentally determined structures. The NF8-01 topology forms a node. (Image: Nobuyasu Koga)

The research team devised rules based on physical chemistry and protein structure data to theoretically predict the likelihood of protein folding. These rules were then used to predict new αβ folds, consisting of four to eight-stranded β-sheets, not yet observed in the current Protein Data Bank (PDB). This led to the identification of a total of 12,356 novel folds. The team then tried to computationally design the protein for new folds predicted from scratch to assess the folding ability and precision of the new folds.

“We are trying to computationally design a protein with all the predicted folds that have a four-stranded β-sheet, including one that forms a knot-like structure,” said Shintaro Minami, a researcher at the Exploratory Research Center on Life and Living Systems (ExCELLS). “When designing proteins, we don’t expect all of them, especially those that form nodes, to fold into the structure as expected.”

The experimental test results are surprising (See Figure). “For all folds, the computationally designed protein structure closely matches the experimental structure,” said Naohiro Kobayashi, senior researcher at RIKEN.

This finding indicates the presence of at least about 10,000 unexplored αβ folds, a significant revelation considering that only 400 αβ folds have been observed in nature. This suggests that many folding potentials remain uncharted in the protein folding space.

These results have given rise to several hypotheses about protein structure and evolution. One hypothesis is that proteins may not have existed in biology long enough for all possible folds to be explored. Another hypothesis is that protein folding in nature is inherently biased because all life on Earth descended from a common ancestor.

“The protein may have evolved by repeatedly reusing certain folds while expressing different functions. If extraterrestrial life does exist, it might use a different set of protein folds,” said George Chikenji, assistant professor at Nagoya University.

Proteins are known for their diverse functions, which result from the diversity of the three-dimensional structure of proteins. This study has revealed the presence of at least about 10,000 uncharted αβ folds in nature.

“This new folded protein design will lead to greater structural diversity. This will pave the way for de novo design of functional protein molecules, leading to breakthroughs in drug development, enzyme design and other fields,” said Nobuyasu Koga, a professor at the Exploratory Research Center on Life and Living Systems (ExCELLS), Institute of Natural Sciences. National (NINS).


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