From Quanta Magazine ( ] Find the original story here ).
Proteins have generally taken precedence over RNA molecules in speculations of scientists on how life on Earth began. Yet a new computer model that describes how early biopolymers could have grown long enough to turn into useful forms could change that. If it continues, the model, which now guides laboratory experiments for confirmation, could restore the reputation of proteins as an original self-replicating biomolecule.
For scientists studying the origin of life, one of the biggest questions about the chicken or the egg is: which proteins or nucleic acids such as l? DNA and RNA are the first? Four billion years ago, the basic elements of chemistry gave rise to longer polymers capable of self-replicating and performing functions essential to life: storing information and catalyze chemical reactions. During most of the life story, nucleic acids have treated previous work and proteins last. Yet, DNA and RNA carry the instructions for making proteins, and proteins extract and copy these instructions as DNA or RNA. Which one could have originally managed both jobs alone?
For decades, the favorite candidate has been RNA - especially since the discovery in the 1980s that RNA can also fold back and catalyze reactions just like proteins. Later, theoretical and experimental evidence supported the "world of RNA" hypothesis that life emerged from RNA that could catalyze the formation of a greater number d & # 39; RNA.
But RNA is also incredibly complex and sensitive, and some experts are skeptical that it could have appeared spontaneously in the harsh conditions of the prebiotic world. In addition, RNA molecules and proteins must take the form of long folded chains to perform their catalytic work, and the early environment would apparently have prevented nucleic acid chains or nucleic acids. amino acids to be quite long.
Ken Dill and Elizaveta Guseva of Stony Brook University in New York, together with Ronald Zuckermann of the Lawrence Berkeley National Laboratory in California, presented a possible solution to the enigma in the Proceedings of the National Academy of Sciences ( PNAS ) this summer. As models go, theirs is very simple. Dill developed it in 1985 to help solve the "protein folding problem," which concerns how the amino acid sequence in a protein dictates its folded structure. His folding model of hydrophobic-polar protein (HP) treats the 20 amino acids as two types of subunits, which he likens to different colored beads on a necklace: blue, aqueous (polar monomer) and red beads, hating water those (non-polar monomers). The model can bend a string of these beads in sequential order along the tops of a two-dimensional network, much like placing them on contiguous squares of a checkerboard. The square that occupies a given pearl depends on the tendency of red and hydrophobic pearls to agglomerate to better avoid water.
Dill, a biophysicist, used this kind of computation throughout the 1990s to answer questions about energy landscapes and protein folding states. It is only recently that he has thought to apply the model to the primitive Earth - and to the transition from prebiotic chemistry to biology. "Chemistry is not interested, and biology is," said Dill. "What were the first seeds of this servitude?"
The answer, he thinks, lies in foldable polymers, or foldamers. With his model, he generated a set of permutations of hydrophobic and polar monomers: the complete assortment of all possible red and blue necklaces up to 25 pearls in length. Only 2.3% of these sequences are reduced to compact foldameric structures. And only 12.7% of these - or just 0.3% of the original set - fold into conformations that expose a hydrophobic spot of red beads on their surface.
This patch can serve as an attractive and sticky landing area for hydrophobic sections of floating sequences. If a single red bead and a red tailed chain land on the hydrophobic patch at the same time, thermodynamics favors the two sequences that bind to each other. In other words, the patch acts as a catalyst to lengthen the polymers, accelerating these reactions up to ten times. Although this rate improvement is small, Dill said, it's significant.
Autoclassatic Origami
Most of these elongated polymers simply continue on their way. But some eventually bend, and some even have a hydrophobic patch of their own, just like the original catalyst. When this happens, the pleated molecules with landing pads not only continue to form more and more long polymers, but they can also constitute what is called an autocatalytic set, in which the foldamers catalyze directly or indirectly the formation of copies of themselves. . Sometimes two or more foldamers may engage in mutual catalysis, reinforcing the reactions that form each other. Although such sets are rare, the number of these molecules would increase exponentially and eventually take precedence over prebiotic soup. "It's like lighting a match and setting a forest on fire," Dill said.
"It's all magic," he added, "the ability of a small event to grow for much larger events."
And all that is needed to trigger this process are special sequences of hydrophobic and polar components that his model can predict. "Dill's model shows that you only need these two properties," said Peter Schuster, theoretical chemist and professor emeritus at the University of Vienna. "It's a nice theoretical result."
"This casts doubt on the vision of the origin of life that is based on the RNA world's hypothesis," said Andrew Pohorille, director of the Center for Research and Development. computational astrobiology and fundamental biology of NASA. For him and other scientists, proteins seem to be a "more natural starting point" because they are easier to make than nucleic acids. Pohorille postulates that the information storage system found in the early rudiments of life would have been less advanced than the nucleic acid-based system in modern cells.
"People did not like the protein hypothesis first because we do not know how to replicate proteins," he added. "This is an attempt to show that even if you can not really replicate proteins in the same way that you can replicate ARN, you can still build and evolve a world without this type of storage." accurate information. "
This fertile environment rich in information could then become more inviting for the emergence of RNA. Since RNA would have been better at autocatalysis, it would have been favored by natural selection in the long run. "If you start with a simpler model [like Dill’s] something like ARN could appear later and become a winner in the production game," said Doron Lancet, a genomics researcher who has worked on his own model based on simple chemistry. the Weizmann Institute of Sciences in Israel.
Searching for evidence with peptoids
Of course, the key to all this lies in the actual experimentation. "Everything that goes back more than 2.5 to 3 billion years is speculation," said Erich Bornberg-Bauer, professor of molecular evolution at Westfälische Wilhelms University in Münster in Germany. He described Dill's work as "really a proof of concept". The model still needs to be tested against other theoretical models and experimental research in the lab if it is really to set up a good fight against the RNA world hypothesis. Otherwise, "it's like the joke about physicists [assuming] cows are perfectly elastic spherical objects," said Andrei Lupas, director of the Department of Protein Evolution at the Max Planck Institute for developmental biology in Germany, which believes in an RNA-peptide world. , in which both have coevolved. "Any meaning ultimately comes from empirical approaches."
That's why Zuckermann, one of Dill's co-authors on the document PNAS began working on a project that, he hopes, will confirm the # Dill's hypothesis.
Twenty-five years ago, when Dill proposed his HP protein folding model, Zuckermann developed a synthetic method for creating artificial polymers called peptoids. He used these non-biological molecules to create protein-imitating materials. Now, he uses peptoids to test HP model predictions by looking at how the sequences fold and if they would make good catalysts. During this experiment, says Zuckermann, he and his colleagues will test thousands of sequences.
It's sure to be messy and difficult. Dill's HP model is very simplified and does not take into account the many complicated molecular details and chemical interactions that characterize real life. "That means we're going to fall into atomic level realities that the model is not able to see," Zuckermann said.
Such a reality might be that a pair of foldamers would aggregate instead of catalyzing the production of the other. Skeptics of Dill's hypothesis fear that it would be much easier for hydrophobic patches to interact with each other rather than with other polymer chains. But according to Pohorille, the potential for aggregation does not automatically mean that Dill is wrong to need these hydrophobic patches to start autocatalysis. "Modern enzymes are not just plain bullets, enzymes contain crevices that facilitate the process of catalysis," he explained.If there is aggregation between the foldamers across their areas. landing, it is possible that the resulting structure may also have such characteristics.
"Although this seems unlikely, science must consider all the assumptions," Bornberg-Bauer added. "That's what Dill does."
For now, at least, the world's RNA hypothesis reigns supreme. Nevertheless, Dill and Zuckermann remain optimistic about what new research will produce. Dill plans to use the model to examine other questions about the origins of life, including how and why the genetic code appeared. And Zuckermann hopes that research - in addition to confirming (or disproving) Dill's calculations - will also help to make foldamers that can serve as vehicles for the delivery of drugs, antibodies synthetic or diagnostic tools.
"This model gives experimenters like me a starting point," said Zuckermann. "He poses the challenge of finding these primitive catalysts, to show how they work, to say: It could have really happened."
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