Crystal Culture – Art down the Microscope

The story begins as any compelling tale should – with a German Scientist, a fluorescent tube, an enigmatic brain and a light dusting of modesty. The conclusion however, is so excitingly far from reach that the applications of crystallography are in their therapeutic infancy.

W.C. Roentgen was the discoverer of X-rays, and the first to coin the idea that electromagnetic waves could be used to visualize bodily structures without the need for anatomical surgery. Miniaturizing this concept to the atomic scale is one of the great medical breakthroughs, owed to the non-eponymously titled X-rays. With crystallography, we can determine elusive 3D structures of proteins by using X-rays to calculate electron density. The molecular blueprints of vaccine development, anti-cancer therapies and pathogenic inhibition lie within the product of purified bio-perfection – the protein crystal.


The conclusion however, is so excitingly far from reach that the applications of crystallography are in their therapeutic infancy.


The road to effective drug development against pathogens, cancers and genetic abnormalities is littered with obstacles. Once we have identified a causative protein the next step is to generate a bank of potential inhibitory compounds. To do this, we need a wealth of structural information on the protein that will inform years of drug development research into pharmacological strategies against the condition. This is where crystallography comes in, and specifically where novel therapeutics call upon the artisan.

Acquiring crystal structures of proteins is no easy feat. Proteins exist in a variable number of structural conformations and some are naturally opposed to crystal formation. Different proteins have a delicate spectrum of experimental conditions that must be achieved to reach a ‘metastable state’ where crystal structures form. The crystallographer’s easel and canvas are the buffer solution, the precipitant and the pH meter, with which a thermodynamic masterpiece must be achieved. See below.




Appreciating the skill involved in modern art has always been a translational miscarriage, but the wealth of biophysical and biomolecular knowledge invested in crystallisation is undeniable. Cubist echoes resonate in the appearance of protein crystals. By transcending the limitations of the canvas, Picasso was able to depict space, mass and time in 2D – a scientific breakthrough in the artistic spectrum. By utilizing the same principal concepts, crystallography is an artistic breakthrough in the scientific sphere. Their beauty lies in the dualism between their form and therapeutic potential. Crystals contain a nebulous and recondite bank of information that can inform the development of life saving drug design.

Electron density is calculated from the diffraction pattern of a rotated protein crystal exposed to X-rays. After a number of vertigo-inducing calculations to overcome the ‘phase problem’, we can model the proteins tertiary structure. The problem is that in the native state, the conformation of proteins is rarely known, and hence crystallization conditions must be as physiologically relevant as possible. After this, screening, molecular dynamic simulations, and ligand docking analysis assess the effectiveness of inhibitory compounds against protein structure.


Their beauty lies in the dualism between their form and therapeutic potential


Vaccination has always been exceptionally challenging due to the conformational flexibility of target proteins, which means antigens can escape inhibition by altering their structure in space. Crystallographic characterisation of vaccine antigen structures has combatted this and hastened the development of many vaccines, determining which areas of the pathogenic protein are accessible for vaccine development.



Research into the structure of the HIV envelope protein has been a forerunner for HIV vaccine development. Schief and co-workers described computational methods that show scaffolds with low conformational flexibility against the versatile HIV proteins gp120 and gp41.

Anti-cancer therapies have utilized crystallography to determine the structure of over-expressed or upregulated enzymes in tumors. Imatinib was developed in this method, and is a therapeutic strategy for inhibiting the defective tyrosine kinase  enzyme in Chronic Myeloid Leukemia (CML).

The art of illuminating atoms to identify protein structure is the first step in drug discovery, an art form in itself.

Featured image courtesy of Max Alexander and STFC, taken from a gallery depicting the work of cutting edge scientists at the Royal Albert Hall.