The evolution of life prefers a single chirality: Why are proteins almost all "left-handed"?

The important substances that make up life have the characteristic of "handedness". Interestingly, DNA and RNA only exist in right-handedness, while proteins are "left-handed". Why does life need chirality? The origin of chirality in life and the preference of life molecules for a single chirality have always puzzled scientists. A recent amino acid synthesis experiment may provide an explanation for the preference of proteins for left-handedness.

Written by Li Na (Researcher at Shanghai Advanced Research Institute, Chinese Academy of Sciences)

In 2005, Science magazine released 125 of the most challenging scientific problems that promote basic scientific research in celebration of its 125th anniversary [1]. In the field of chemistry, it raised the soul-searching question of “Why does life require chirality?” (Figure 1). How did the chirality of life originate? Why does life evolution prefer a single chirality? These are two major mysteries in exploring the origin of life.

Figure 1. Science 125 frontier scientific questions: "Why does life need chirality?"

What is Chirality?

The term "chirality" comes from the Greek word "cheir", which means "hand"; as the name suggests, it refers to the difference between the left hand and the right hand.

Figure 2. A person's left and right hands are mirror-symmetrical and cannot overlap, so they have chirality; the bottle is axially symmetrical and has no chirality.

Understanding this difference is actually very simple. You only need to put your right palm down, and then put your left palm down on top of your right hand. You will find that the two hands that seem to be the same cannot actually overlap completely. This shows that your left hand and right hand are "handed". Observe more carefully, your left hand and right hand are actually a mirror image of each other. Your right hand cannot overlap with the mirror image of your right hand, but can only overlap with the mirror image of your left hand. Similarly, your left hand can only overlap with the mirror image of your right hand. This explains why when you put your hands together, your left and right hands can overlap perfectly (Figure 2). Through the observation of "hands", I believe you can understand that anything that cannot overlap with its own image in the mirror is said to have handedness [2].

Chirality is very common in daily life, such as the threads of snail shells on the beach, screws, screw-mouth light bulbs, and drill bits, spiral staircases in star-rated hotels, and even typhoons that cause natural disasters. This characteristic not only exists in the macroscopic natural world, but also in microscopic life activities, which all rely on the chirality of molecules.

On Earth, important organic molecules that make up life usually have chirality. Interestingly, life forms show an extreme selection bias for the configuration of these basic units of organic molecules. For example, the genetic codes of life, DNA and RNA, are both right-handed; while proteins, the important "elements" of life, are mostly left-handed (glycine is chiral), which is what we often call "left-handed" (Figure 3). The situation in which a certain chiral configuration of the same type of molecules exhibited by life forms accounts for the majority is usually called "homochirality".

Figure 3. Chirality is a fundamental property of nature. DNA and RNA molecules are both right-handed, while protein molecules are mostly left-handed.

Two hypotheses explain the mystery of the chirality of life

Regarding the origin of chirality of biological molecules, in recent decades, some scientists have believed that the important organic molecules that make up life were first created in outer space and then came to Earth with meteorites. In 1969, a meteorite weighing about 100 kilograms was discovered near Murchison, Australia [3]. After elemental analysis, it was found that it contained more than 90 important molecules that make up life, including organic molecules such as amino acids, sugars, and alcohols; and among the amino acid molecules detected, left-handed amino acids accounted for the majority.

So how did chirality form in space? One hypothesis is that it may be due to the spin effect of circularly polarized light (CPL) emitted by stars in space. CPL is divided into left-handed and right-handed [4]. Chiral molecules absorb left-handed and right-handed light differently. The stronger the absorption ability, the faster the chemical reaction occurs. The contents of meteorites were exposed to single-chirality CPL in outer space for a long time, which eventually led to different ratios of left-handed and right-handed organic molecules in them, and organic molecules of a certain chirality continued to accumulate in a large space. Cosmic dust with excess enantiomers [Note 1] of organic molecules continued to aggregate to form comets and meteorites, and eventually passed through the Earth's atmosphere when the Earth was close to their orbits and collided with the Earth, bringing the first chiral organic molecules to the Earth (Figure 4).

Figure 4. Australian Murchison meteorite and a model of the hypothesized cosmic origin of chirality.

Another hypothesis is that the chirality of biomolecules originates from chiral-induced spin selectivity (CISS), according to a new study recently published in the Proceedings of the National Academy of Sciences (PNAS) [5].

The spin of an electron is a quantum property that exists in one of two possible angular momentum states, often referred to as "spin up" or "spin down." Chiral molecules[note 2] "scatter" electrons according to the direction of their spin rotation. This way, electrons with the same spin state are concentrated at the polarity of the chiral molecule, and the left-handed and right-handed versions of a molecule have electrons with opposite spin states at their respective polarities. But this redistribution of electrons affects how chiral molecules interact with other molecules (electrons with opposite spins attract each other, and electrons with the same spin repel each other). So when a chiral molecule approaches a magnetic surface, if the molecule and the surface have opposite spins, they are pulled closer together; if they have the same spin, they repel each other.

Scientists believe that the CISS effect on magnetite leads to the origin of molecular chirality: 1.8 billion to 3.7 billion years ago, the Earth formed abundant underwater sedimentary magnetite deposits in an oxygen-deficient environment, and ultraviolet radiation on the Earth's surface caused spin-polarized photoelectrons to be produced in the uniformly magnetized magnetite. Due to the CISS effect, enantioselective chemical reactions of bioorganic molecules occurred on the surface of magnetite, and different chiral organic molecules were screened out, initiating the process of making biomolecules such as DNA, RNA, and amino acids become asymmetric.

Why does the creation and evolution of life molecules prefer "left-handed"?

Let's assume for the moment that some "external force" gave the molecules the initial tendency towards chirality. Then, during the long evolution of the Earth, what factors caused the basic structural unit of life - amino acid molecules - to evolve further and further into "left-handed"?

Matthew Powner, an origin of life chemist from University College London, and his colleagues have provided clues to this question. Over the past five years, Powner's team has discovered a group of sulfur-based molecules that may have existed on the early Earth, and demonstrated how they effortlessly linked single amino acids to amino acid precursors, aminonitriles, to form dipeptides [Note 3]. Dipeptides play an important role in life, not only participating in the construction of functional protein molecules, but also acting as signaling molecules to regulate physiological processes such as metabolism, growth, and development. More importantly, dipeptide molecules are chiral. As we have learned before, except for a few animals, algae, and seed plants that contain a small amount of right-handed amino acids (such as right-handed alanine and right-handed glutamic acid on the peptidoglycan of the cell walls of many bacteria), the amino acids that make up life on Earth are almost all left-handed. Since dipeptide molecules are formed by the connection of a single amino acid with an amino acid precursor, aminonitriles, the chirality of aminonitriles can be regulated by chemical synthesis methods, understanding the origin of dipeptide chirality helps us understand the choices in the evolution of life molecules.

The dipeptide synthesis reaction by Powner's team takes place in water and works with all the amino acids found in living organisms, so this work provides a plausible experimental path to reveal how the first proteins formed. However, Powner's team did not check whether the sulfur-based catalysts they prepared had a chiral bias.

Until February 2024, Donna Blackmond, a chemist at the Scripps Research Institute in the United States, and her colleagues published a research report in Nature [6]. They used optimized reaction conditions to achieve a catalytic peptide connection reaction between aminonitriles and amino acids, producing two enantiomer dipeptide products; the enantiomeric ratio of the product is defined as the relative concentration of heterochiral and homochiral dipeptide products in the stereocenters of the two products. By monitoring the formation rate of amino acid pairs of dipeptides under different experimental conditions (single chiral molecules, different combinations of single chiral molecules and racemic reactants, different catalysts), the Blackmond team found that the catalytic peptide connection reaction tends to produce heterochiral dipeptide products (i.e., L monomers connected to D monomers), and symmetry breaking, chirality amplification, and chirality transfer will occur in complex reaction mixtures. Although the catalytic peptide reaction tends to be heterochiral, this choice provides a mechanism for the generation of homochiral dipeptide products and chiral enrichment of unreacted substrates in experiments. The team further combined kinetic computational simulations to predict that the catalytic peptide ligation reaction tends to produce a dipeptide product with homo-left-handedness, which is consistent with the experimental data (Figure 5).

Although this mechanism for driving the chirality of bioorganic molecules has only been confirmed in dipeptides, Blackmond said that preliminary work shows that the same chiral selection process occurs when sulfur catalysts connect short peptides into longer peptide chains. This discovery not only provides a new perspective for our understanding of the origin of life, but also provides new ideas for exploring possible life forms on other planets.

Figure 5. Laboratory strategy for preparing completely left-handed dipeptides based on sulfur-based molecules.

Chiral molecules determine human survival

Imagine that humans discovered a planet that favors "right-handed people" during interstellar exploration. The geographical conditions and climate environment on this extraterrestrial planet are exactly the same as those on Earth. Can humans survive on this planet? Undoubtedly, the answer is no. Because the organisms on Earth are composed of left-handed amino acids, they cannot metabolize right-handed molecules well. If all the life molecules on this extraterrestrial planet are right-handed molecules, they are "waste" that cannot be used for our Earth life, and may even be poison. In the 1960s, a chiral drug called "Thalidomide" (thalidomide) caused pregnant women who took the drug to give birth to 15,000 deformed fetuses with short limbs like seals because it concealed a pair of chiral isomers "twin sisters" (the right-handed isomer has a sedative effect, and the left-handed isomer has a strong teratogenic effect). This is a major tragedy in the history of drug discovery and an important turning point in the history of pharmaceutical manufacturing.

Chiral amino acid molecules determine how we exist on Earth. Scientists' research on the "left-handed" characteristics of protein molecules in the process of life evolution provides a key to unlock the mystery of the origin of life. Just as Leonardo da Vinci, a famous "left-handed" artist in the Renaissance, was proud of his "mirror writing method" (writing from right to left, and each letter is reversed; the mirror writing content needs to be reflected by a mirror to be read), it has left us with inspiration - changing the angle and way of thinking about the problem may get closer to the essence of the problem.

Figure 6. The slogan for the International Day of Left-Handedness and Leonardo da Vinci’s mirror-written manuscript in the Codex Atlanticus.

Terminology Notes

1. Enantiomers: Stereoisomers that are mirror images of each other. They have the same molecular formula but different spatial arrangements. One of the molecules that are enantiomers is left-handed and the other is right-handed.

2. Chiral molecule: refers to a molecular structure with a chiral center, where the chiral center is usually a carbon atom (chiral carbon atom) connected to four different atoms or groups.

3. Dipeptide: A dipeptide is a molecule composed of two amino acid residues connected by a peptide bond. It has important physiological functions and can be constructed into isomers of different chirality by regulating chemical synthesis methods.

References

[1] 125 questions: Exploration and discovery | Science | AAAS

[2] Chirality, wikipedia.org

[3] https://www.sciencedirect.com/topics/earth-and-planetary-sciences/murchison-meteorite

[4] M.Avalos, R. Babiano, P. Cintas, JL Jiménez, JC Palacios, LD Barron, Absolute asymmetric synthesis under physical fields: facts and fictions. Chem. Rev. 1998, 98, 2391–2404.

[5] SF Ozturk, DD Sasselov, On the origins of life's homochirality: Inducing enantiomeric excess with spin-polarized electrons. Proc. Natl. Acad. Sci. USA 2022, 119:28, e2204765119

[6] M. Deng, JH Yu, DG Blackmond, Symmetry breaking and chiral amplification in prebiotic ligation reactions. Nature. 2024, 626, 1019-1024

This article is supported by the Science Popularization China Starry Sky Project

Produced by: China Association for Science and Technology Department of Science Popularization

Producer: China Science and Technology Press Co., Ltd., Beijing Zhongke Xinghe Culture Media Co., Ltd.

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