Left-handed or right-handed?

Crystal chirality and the asymmetry of life

Crystals of biominerals like the ones in bone or teeth oftentimes occur only either in a left- or right-handed form, which relate to each other like an object and its mirror image. How this “chirality” is conferred to these otherwise achiral crystals is poorly understood. Now an international team of researchers led by Empa scientists has shown for the first time how chiral biomolecules imprint their handedness on crystal surfaces at a molecular level, as they report in “Nature Chemistry”.
An example of single-crystalline calcite: achiral rhombohedral island spar

The lack of mirror symmetry – that is, structures appear either only in a left- or right-handed fashion – is a striking property of the biological world. This so-called homochirality is seen at the molecular, cellular and even at the macroscopic level. Snails are a classical example, having spiral shells that revolve almost entirely in a clockwise direction for a given species. Other well-known examples are found in the direction of twining of various climbing plants or the position of organs in the human body.
Less known is the fact that single crystals of biominerals like calcite or calcium oxalate possess a handedness only because they grew in a biological environment where the molecules of life (sugars, proteins) install their own chirality onto the otherwise achiral mineral. There are many examples of chiral shapes in biologically formed minerals but how chiral information is transferred from biomolecules to crystalline surfaces is poorly understood.
Now an international research team involving experts from Switzerland, China, Hungary, UK, Italy, and the US and led by Empa scientists published a study in “Nature Chemistry” that explains in great detail how a chiral molecule reshapes a crystal surface, in other words: how handedness is transmitted to otherwise achiral structures and what the underlying mechanism is at the atomic level. Investigating why crystals of achiral minerals obtain a chiral shape – that is, a structure that can be superimposed only onto their mirror images –, the research team placed chiral molecules onto a metal surface and showed how it became re-shaped due to the molecule-surface interaction by scanning tunneling microscopy (STM) analysis at submolecular resolution combined with synchrotron radiation X-ray photoelectron diffraction (XPD) – a feat that had never been achieved before.

Paving the way for new drugs
Another example of single-crystalline calcite: coccoliths, exoskeletons of unicellular algae. The round distal plates of Calcidiscus leptoporus exhibit a handed pinwheel shape. Copyright: Nanotax, Calcidiscus leptoporus subsp. quadriperforatus (Kamptner 1937) Geisen et al., 2002

Karl-Heinz Ernst, Distinguished Senior Researcher at Empa and Professor of Chemistry at the University of Zurich, one of the authors of the paper, explains: “Understanding the formation of asymmetrical shapes during the growth of otherwise symmetrical crystalline structures is one step towards understanding asymmetry in biology. Crystals of biominerals like those of bones, teeth, shells or sea urchin spines are being shaped with remarkable control,” he adds. “But it is poorly understood how biomolecules exactly interfere with the crystal growth at the crystal surface.”
By using a well-defined model system the researchers could show how a single (chiral) organic molecule – a hemibuckminsterfullerene or ‘buckybowl’, that is, half a buckyball or C60 molecule – dictates where the atoms of the mineral are placed in its vicinity on the surface and thus, transfers its left- or right-handed nature, that is, its chirality, to the crystal structure, in this case a copper surface. This process in known as “molecular tectonics”.
Roman Fasel, head of Empa’s nanotech@surfaces laboratory and Adjunct Professor at the Department of Chemistry and Biochemistry at the University of Bern, who led the study, adds: ”Single-handed metal surfaces are of considerable interest in enantioselective heterogeneous catalysis – a chemical strategy to produce single-handed molecules in a highly selective way. Our work reveals an easy way to obtain such surfaces, simply by adsorbing a specific single-handed molecule that re-shapes the metal into the desired chiral morphology.”
It must be noted, however, that the present results only provide a proof-of-principle – to put this into practice, the challenge will be to identify a suitable molecule that creates the specific metal surface morphology that will bring about the desired catalytic reaction. That is not an easy task by any means, but the present work is likely to stimulate efforts along these lines.

Chirality and drug development – the Thalidomide tragedy

Chirality – or ‘handedness’ – is a striking property of the biological world. Many organic molecules, including glucose and most biological amino acids are chiral and the DNA double helix in its standard form twists like a right-handed screw.
The importance of chirality in biological systems was brought to light in a devastating way by the Thalidomide tragedy. Thalidomide was prescribed widely to pregnant women between 1957 and 1962 for its benefits in reducing morning sickness. However, when taken during the first trimester of pregnancy, Thalidomide prevented the proper growth of the fetus, which resulted in thousands of children around the world being born with severe birth defects.
Thalidomide is a chiral molecule and the drug that was marketed was a 50/50 mixture of left- and right-handed molecules. While the left-handed molecule was effective, the right-handed one was highly toxic. “Thalidomide has later been identified as an efficient anti-cancer and anti-leprosy drug. It is still prescribed as 50/50 mixture of both isomers, because the beneficial isomer is converted into the toxic one in the human body, so separation is useless”, explains Ernst. “But it is a tragic example about the different biomedical effects the antipodes of chiral drugs may have.”
The essential oil carvone is another one of many examples where the right- and left-handed forms of the molecule act differently – one mirror isomer smelling like caraway, the other like spearmint.
“We now aim at further understanding the process of chiral induction and hope that such new insights will help us to define new functional materials or catalysts for drug synthesis in the future,” concludes Fasel.

Microscopic origin of chiral shape induction in achiral crystals, W Xiao, KH Ernst, K Palotas, Y Zhang, E Bruyer, L Peng, T Greber, W Hofer, L Scott, R Fasel, Nature Chemistry, 2016, DOI: 10.1038/NCHEM.2449