Crystallography, a foundation block of science today.

By Beatrix Watson-Smyth


Today X-Ray Crystallography is widely used for drug discovery and virus research, including the mapping of the novel surface proteins of SARS-CoV 2, also known as Coronavirus.

X-ray Crystallography is the most successful and widely used method to discover the structure of proteins. The underpinning field was first discovered in 1912 by Max Von Laue, who saw that the diffraction of the x-ray waves could be used to find ‘the underlying order of atoms in the crystal’. This was taken further by Willaim Henry Bragg and Lawrence Bragg who made the first application of this theory to find molecular structures. In principle, X-ray waves are shined on to a crystal and the diffraction the crystal causes is measured. This picture can then be used to work backwards to the molecular arrangement inside the crystal, due to the orderly repeating pattern. 



During an interview, Glazer points out that 28 Nobel prizes, at a minimum, can be accredited at least in part to Crystallography, revealing its large impact on the scientific community. Perhaps the most famous example of crystallography is found in photo 51, the diffraction of DNA fiber taken under supervision on Rosalin Franklin. This was used to discover the double helix structure of our DNA, by Watson and Crick in 1953.

Photo 51


Crystallography has become so commonplace in the lab, it is now seen as routine science and uninteresting. However, this is misrepresentative of the field. Crystallography has had some groundbreaking advances in the 21st century, such as the development of electron crystallography and a future in quantum theory. Quantum Crystallography is a newly emerging field, so new that the definition of ‘Quantum Crystallography’ has not even been fully agreed upon. It can be used in further research of quantum phenomena such as chemical bonding, and wave function calculations, as well as revealing electron densities, mostly in crystalline structures.

However, there are disadvantages of X-ray Crystallography which limit its use. The proteins it images have to be crystallised, which is sometimes impossible, meaning scientists must look elsewhere. Furthermore, some protein have been known to charge shape apon crystallisation, which causes the process to be redundant. 


Today, Crystallography is fundamental in drug discovery, due to the technique of structure based drug discovery being commonplace in labs today. This means labs often design new proteins, or ligands, with specific receptor sites that bind to the target protein. When these ligands bind and form a ligand protein complex they produce a signal if successful binding occurs. This alerts the lab to the affinity of the binding, due to the strength of the signal. This design of a successful ligand would be impossible without the scientist being able to choose a possible site on the target protein that would change its shape and therefore function. To identify the structure of possible binding sites is the job of crystallography, as well as being able to see the effects of successful binding on the shape of the target protein, after a complex is formed. 

This is very helpful in research of viruses, such as Influenza. Crystallography plays a large role in identifying the different types, and the accompanying shapes, of neuraminidase and hemagglutinin. These are the two surface proteins which allow the virus to enter the cell, release its RNA into the cell, as well as exit the cell and release it from the cell's membrane to infect other cells. Antibodies that have a high affinity to these antigens bind to form antibody antigen complexes. This prevents the surface proteins from facilitating the virus infecting the cell or, depending on which antigen targeted, leaving the infected cell to infect other cells.

Another application of crystallography in the lab was revealing the distinctive structure of the HIV capsid and the surface proteins. This particular application allows much research into possible cures and therapy drugs, opening new research lines into the evasive virus. 


Crystallography is not a field of science to be overlooked and can be employed for a large variety of different fields, as well as form the foundation of biomedical drug discovery today.The rich history of crystallography in the 20th century will not be the high point of the field. 


References:

www.ndm.ox.ac.uk. (n.d.). Part 2: The history of structural biology - Nuffield Department of Medicine. [online] Available at: https://www.ndm.ox.ac.uk/part-2-the-history-of-structural-biology [Accessed 6 Apr. 2020].

Glazer, A.M. (2016). A brief history of crystallography. [online] OUPblog. Available at: https://blog.oup.com/2016/05/a-brief-history-of-crystallography/.

www.ndm.ox.ac.uk. (n.d.). Part 2: The history of structural biology - Nuffield Department of Medicine. [online] Available at: https://www.ndm.ox.ac.uk/part-2-the-history-of-structural-biology [Accessed 6 Apr. 2020].

 Zimmermann,Sophie and Gul,Sheraz (2017). Structure based drug discovery facilitated by crystallography. Drug Target Review, [online] 4(3), pp.9–13. Available at: https://www.drugtargetreview.com/article/25495/structure-drug-discovery-crystallography/ [Accessed 8 Apr. 2020].

https://www.chemistryviews.org/details/ezine/11072600/What_Is_Quantum_Crystallography.html

https://www.ncbi.nlm.nih.gov/pubmed/28842649

https://leapsmag.com/why-havent-researchers-developed-an-hiv-vaccine-or-cure-yet/

https://onlinelibrary.wiley.com/doi/abs/10.1002/9780470015902.a0002716.pub2

https://www.sciencedirect.com/topics/biochemistry-genetics-and-molecular-biology/x-ray-crystallography

https://study.com/academy/lesson/what-is-a-ligand-in-cell-biology.html


The most important photo ever taken? http://www.bbc.co.uk/news/health-18041884