The sequencing of the human genome provides exciting possibilities to explain the complexities of life. But some more basic questions remain unanswered — such as why the double-helix structure of DNA spirals in a clockwise (right-handed) direction, rather than a left-handed one. On page 797 of this issue1, Ghadiri et al. use a peptide system to demonstrate how 'homochirality', or single-handedness, may have evolved in biological molecules.
Nucleic acids, like nearly all biological molecules, exhibit 'handedness', and only one of the two forms is used in a particular biological process. This gives rise to homochirality, where each molecule is identical. Among sugars, ribose and deoxyribose are not identical; nonetheless, the form of ribose in RNA and the form of deoxyribose in DNA share a common right-handed orientation of their principal functional groups. This common stereochemistry — the three-dimensional shape of the molecule — evokes another concept of homochirality, which relates members of a family of compounds.
The natural amino acids share a common stereochemistry, as they are all left-handed (l-amino acids). This raises the question of whether homochirality within a family of biological molecules is the result of a stereochemical cooperativity (diasteroselectivity) among the members within a biopolymer. Indeed, our enzymes and nucleic acids are composed of predominantly l-amino acids and d-sugars — we are unable to use the opposite-handed bioploymers. Why not? Attempts to answer this question by mimicking the creation of a homochiral environment in the laboratory have been unsuccessful until now.
This difference in functional chiral form had tragic consequences in the 1960s when pregnant women were given a sedative (Thalidomide) that was a mixture of the right- and left-handed forms of the drug; one of the two forms, or enantiomers, gave rise to birth defects. That two enantiomers can have such different functions shows that stereochemistry controls whether, and how, molecules recognize one another and 'shake hands'.
The origin of one-handedness in biological molecules is not yet clear2. Several explanations have been put forward to explain how homochirality came about, but all are speculative — it is not even known yet whether it arose by chance or by some other means3, 4.
Synthetic polymers are simpler than biological systems and provide a model for understanding the origin of homochirality in biomolecules. One proposal stems from observations that polymers made from building blocks of random handedness will contain mixtures of right- and left-handed blocks so complex that no two polymers will have identical stereochemistry. All the polymers will be chiral, but if one exists, it is unlikely that its mirror image will too5. For small polymers consisting of only a few building blocks, the number of possible combinations of right- and left-handed blocks is small, and the mirror images are easily formed. However, for a polymer comprising 20 building blocks there are almost a million possibilities, and an enormous number of blocks would be required to build all the possible mirror images. Biological molecules often have over 100 building blocks, pushing the limits of available materials and making it extremely unlikely that a molecule and its mirror image can be prepared in the same batch. If the sample of polymers contained some that were self-replicating, it is reasonable that the most efficient one will emerge, and only this homochiral polymer will exist6.
In complex organisms and living systems, homochirality manifests itself in families of related biological molecules, such as the naturally occurring l-amino acids in a protein. The presumption here is that there is cooperativity among these biomolecules in their biopolymers or underlying structure. The polymer example above alludes to an optimum self-replicating polymer. Can we form a general rule that homochirality leads to optimal function? With regard to self-replication, this question can be addressed by stereochemical analysis and reaction engineering. However, engineering the parameters of biochemical processes to obtain appropriate stereoselectivity — choosing of the preferred mirror image — has not been trivial. Poor reaction selectivity and inhibition of replication have plagued researchers who would like to mimic life through protobiology7.
Ghadiri et al.1 find a stereoselective reaction, between two chiral peptides, that uses the product of their coupling to replicate — a process known as 'autocatalysis'. Their results indicate that this self-replicating system could perpetuate homochirality, because a left-handed template is competent to bring together only those fragments that are also left-handed. The authors also show that, even if only one out of 15 building blocks has opposite handedness, autocatalysis is significantly diminished. Such a result establishes that homochiral peptides are most efficient at autocatalysis.
The authors also found that even though a single 'mutation' with regard to handedness could hamper autocatalysis, the same mutant template was reasonably effective at catalysing the combination of two pure left-handed fragments. The combination of these results supports the idea that a polymer evolution experiment would ultimately result in homochirality of biological molecules. Furthermore, these results support a general principle that similarity in building blocks leads to higher-order structure, like the spiral shape of a ram's horn or a crystal-lattice structure8, 9.
Given the fundamental nature and pervasive occurrence of chirality in biological and non-biological macromolecules, it is reasonable to postulate that homochirality existed long before the genetic information of life was encoded. Once in place, this sense of chirality perpetuated throughout early life systems and has become a part of complex biochemical processes such as translation and transcription. So the linear sequence of information on the genome is passed along owing to the three-dimensional structure of the DNA double helix, and must now include the coding for homochirality that we see in amino acids. We now have a model system that may bring us closer to understanding why we see cooperativity among homochiral biological molecules today.
