The assembly of molecules into supramolecular architectures is influenced by various triggers such as light, temperature, pH, and chemical signals. Recently, researchers have found that chemical fuels can induce molecules to self-assemble into alternate structures, depending on the chirality of these fuels. This may help explain the origins of homochirality in life—especially within peptides and proteins.
‘Altering the chirality of [chemical] fuels results in distinct three-dimensional structures,’ states senior author Charalampos Pappas from the University of Freiburg in Germany. ‘This enhances our capacity to engineer synthetic systems with lifelike behaviors [and] could be significant for understanding the origins of homochirality.’
The German research team examined acylation, a prevalent reaction that ‘activates’ peptides, leading to a chemical transformation that initiates phenomena such as self-assembly. However, when a chiral peptide interacts with a chiral acylating agent, the resulting reaction produces two diastereomeric structures that possess varying physicochemical characteristics. ‘[Such] supramolecular assemblies exhibit markedly different formation kinetics … in addition to varied structural morphologies and mechanical traits,’ remarks Jeanne Crassous, a specialist in supramolecular chemistry and chirality at the CNRS Institute for Chemical Sciences in Rennes, France, who did not participate in this research. The team subsequently characterized these supramolecular self-assemblies employing an extensive array of techniques, such as fluorescence and electron microscopy for morphology investigation, and liquid chromatography–mass spectrometry for assessing the stability of the structures.
‘Employing the left-handed acylating agent results in an activated peptide with a dissimilar 3D configuration compared to the structure created by the right-handed fuel,’ states Lenard Saile, who co-led the initiative alongside Kun Dai. ‘Picture the peptide forming a sphere when energized with the left-handed [reagent] and a sheet with the right-handed one,’ he continues. ‘While sheets stack effortlessly, spheres typically cannot and remain dispersed.’
In a similar vein, the diastereomeric self-assembled structures exhibit considerably different behaviors. In fact, their stability and resistance to hydrolysis also differ. This presents an opportunity to modulate reactivity and create ‘chemical computers’ and processes ‘fine-tuned by intricate stereochemical information,’ clarifies Saile. ‘Combined with other reactions and stimuli, chemists could develop compartmentalized systems that [mimic] metabolism and reproduction.’
Acylation reactions serve as essential biochemical building blocks that govern protein behavior within the cell. ‘For instance, the acylation of histones controls gene expression,’ notes Saile. ‘Interestingly, most biological acylation processes involve an acyl phosphate as the activated acyl donor,’ he adds. ‘This is the reason we selected [chiral] acyl phosphates as biomimetics,’ he explains—to gain deeper insight into these systems. Such self-assembly mechanisms, prompted by regulated chiral acylation, are synthetic and ‘not employed by natural systems,’ according to Saile. Nonetheless, the revelation of a connection between chirality and chemically regulated self-assembly might reveal intriguing hypotheses regarding homochirality in living organisms.
‘One type of handedness leads to more resilient and organized assemblies than the other, suggesting that chirality … might have influenced the characteristics of primitive supramolecular structures,’ elucidates Claudia Bonfio, a specialist in the origins of life at the University of Cambridge, UK. ‘This transitions the discussion of chirality from individual molecules to larger supramolecular assemblies.’