Molecules often have a structural asymmetry called chirality, which suggests they’ll appear in alternative, mirror-image versions, akin to the left and right versions of human hands. Certainly one of the nice mysteries concerning the origins of life on Earth is that virtually all of the elemental molecules of biology, resembling the constructing blocks of proteins and DNA, appear in only one chiral form.
Scripps Research chemists, in two high-profile studies, have now proposed a chic solution to this mystery, showing how this single-handedness or “homochirality” could have turn into established in biology.
The studies were published within the Proceedings of the National Academy of Sciences on February 5, 2024, and in Nature on February 28, 2024. Together, they suggest that the emergence of homochirality was due largely to a chemistry phenomenon called kinetic resolution, through which one chiral form becomes more abundant than one other as a result of faster production and/or slower depletion.
“There have been many proposals for a way homochirality emerged in specific molecules — specific amino acids, for instance — but we actually have needed a more general theory,” says Donna Blackmond, PhD, professor and John C. Martin Chair within the Department of Chemistry at Scripps Research, who led each studies.
Graduate student Jinhan Yu and postdoctoral research associate Min Deng, PhD, were the primary authors of the 2 studies.
The conundrum of homochirality
“Origin of life” chemistry has been a busy field for much of the past century. Its practitioners have discovered dozens of key reactions that plausibly occurred on the early, “prebiotic” Earth to provide the primary DNAs, RNAs, sugars, amino acids and other molecules that sustain life. Missing from this body of labor, nonetheless, has been a plausible prebiotic theory for the emergence of homochirality.
“There was a bent in the sphere to disregard the chirality issue when searching for plausible reactions that might have made the primary biological molecules,” Blackmond says. “It’s frustrating, because without reactions that favor homochirality, we would not have life.”
Abnormal chemical reactions that produce chiral molecules are likely to yield equal (“racemic”) mixes of left- and right-handed forms. Outside of biology, this mixing typically doesn’t matter, as each forms often have similar or equivalent properties. Inside biology, though, as a consequence of intensive homochirality, it is often the case that only the left- or the right-handed type of a chiral molecule has useful properties — the opposite could also be inert and even toxic. Thus, cells often guide reactions to yield specific chiral forms, using highly evolved enzymes.
The prebiotic Earth wouldn’t have had such enzymes, though — so how did homochirality ever arise?
A paradoxical result
Of their study in Proceedings of the National Academy of Sciences, Blackmond and her team addressed this problem for amino acids. These small organic molecules are used as constructing blocks for proteins by all living things on Earth, but exist in biology in only the left-handed chiral form.
The researchers specifically sought to breed homochirality in a central process in amino acid production called transamination, by utilizing a comparatively easy, plausibly prebiotic chemistry that excludes complex enzymes.
In early tests, the team’s experimental response worked, and yielded amino acids that were enriched for one chiral form versus the opposite. The issue was that the favored form was the right-handed form — the one which biology doesn’t use.
“We were stuck for some time, but then the sunshine bulb went on — we realized we could do a part of the response in reverse,” Blackmond says.
After they did that, the response now not preferentially made right-handed amino acids. In a striking example of kinetic resolution, it as an alternative preferentially consumed and depleted the right-handed versions — leaving more of the specified left-handed amino acids. It thus served as a plausible path to homochirality for amino acids utilized in living cells.
Tying all of it together
For the Nature study, the chemists explored an easy response with which amino acids within the earliest life forms may need been linked together into the primary short proteins (also referred to as peptides). The response had been published earlier by one other researcher, but had never been investigated for its ability to provide homochiral peptides from racemic or near-racemic mixes of amino acids.
Once more, the chemists bumped into what gave the impression to be an insurmountable obstacle: They found that in forming peptide chains of amino acids, the response worked faster for linkages of left-handed with right-handed amino acids — the alternative of the specified homochiral peptides.
Still, the team persevered. Ultimately, they found that when one sort of amino acid within the starting pool of amino acids had even a moderate dominance of the left-handed form — as their other study made plausible — the faster response rate for left-handed-to-right-handed linkages preferentially depleted right-handed amino acids, leaving an ever-greater concentration of left-handed ones. Moreover, the left-right-left-right peptides had a stronger tendency to clump together and fall out of solution as solids. These kinetic resolution-related phenomena thus ended up yielding a surprisingly pure solution of virtually fully left-handed peptides.
To Blackmond, the seemingly paradoxical mechanisms uncovered in these studies offer the primary convincing and broad explanation for the emergence of homochirality — an evidence that probably works not just for amino acids, she says, but additionally for other fundamental molecules of biology resembling DNA and RNA.
Funding for each studies was provided by the Simons Foundation through the Simons Collaboration on the Origins of Life (SCOL 287625), and thru the John C. Martin Endowed Chair in Chemistry at Scripps Research.
