Chirality, a structural asymmetry commonly found in molecules, often gives molecules mirror-image appearences, similar to left and right hands. One of the enduring puzzles surrounding the origins of life on Earth is the prevalence of just one chiral form in the fundamental molecules of biology, including the building blocks of proteins and DNA. But briefly, the DNA helix only turns one way.

Now Scripps Research chemists have unveiled an elegant solution to this enigma through two landmark studies, shedding light on the establishment of homochirality in biology.

Published in the Proceedings of the National Academy of Sciences on February 5, 2024, and in Nature on February 28, 2024, the studies propose that the emergence of homochirality can be largely attributed to a phenomenon in chemistry known as kinetic resolution. This process involves one chiral form becoming more abundant than the other due to differential rates of production and/or depletion.

"There have been many proposals for how homochirality emerged in specific molecules—specific amino acids, for example—but we really have needed a more general theory," says Donna Blackmond, PhD, professor and John C. Martin Chair in the Department of Chemistry at Scripps Research, who led both studies.

Graduate student Jinhan Yu and postdoctoral research associate Min Deng, PhD, served as the first authors of the two studies.

The Oddity of Homochirality

The field of "origin of life" chemistry has been active for decades, uncovering numerous reactions that could plausibly have occurred during Earth’s earliest days to generate the molecules essential for life. However, a missing piece has been a credible “prebiotic” theory for the emergence of homochirality.

"There has been a tendency in the field to ignore the chirality issue when looking for plausible reactions that could have made the first biological molecules," Blackmond explains. "It’s frustrating, because without reactions that favor homochirality, we wouldn't have life."

While ordinary chemical reactions typically yield equal mixes of left- and right-handed chiral forms, the prevalence of homochirality in biology underscores the significance of specific chiral forms. Cells often direct reactions to produce these specific forms, leveraging highly evolved enzymes.

However, the prebiotic Earth lacked such enzymes, raising questions about how homochirality originated.

Contradictory Results

In their study published in the Proceedings of the National Academy of Sciences, Blackmond and her team tackled this challenge concerning amino acids. These molecules, crucial as protein building blocks, exist in biology predominantly in the left-handed chiral form.

The researchers aimed to replicate homochirality in amino acid production through a relatively simple, prebiotically plausible chemistry devoid of complex enzymes.

Initially, the experimental reaction favored the right-handed form of amino acids—a form not utilized in biology—posing a setback. However, through a reversal of part of the reaction, known as kinetic resolution, the reaction began to favor the desired left-handed amino acids. This process provided a feasible pathway to homochirality for amino acids crucial in living cells.

Fitting the Pieces

In their Nature study, the chemists investigated a basic reaction that could have linked amino acids in early life forms to form the first peptides. Although the reaction initially favored linkages between left- and right-handed amino acids—contrary to the desired homochirality—the team persisted.

Ultimately, they found that when a moderate dominance of left-handed amino acids existed in the starting pool, the reaction preferentially depleted right-handed amino acids, yielding nearly pure left-handed peptides.

To Blackmond, these seemingly paradoxical mechanisms uncovered in the studies offer a compelling explanation for the emergence of homochirality—a theory likely applicable not only to amino acids but also to other fundamental molecules of biology, such as DNA and RNA.

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