From Crystallography to Light (according to the United Nations)

Those of you who started the PPS course in 2014 may not have realised that they began their studies of structural biology at an auspicious time for this subject. Last year was designated the International Year of Crystallography to mark the centenaries of both the discovery of X-ray diffraction by crystals (first published in 2013) and the award, in 2015, of the Nobel Prize to the father-and-son team of William and Lawrence Bragg who made the discovery. I have blogged about this in much more detail over the previous year, with a post in December 2013 on "a very short history of crystallography" and one in July reporting on lectures by two of our distinguished emeritus professors, Paul Barnes and David Moss. Professor Moss took the subject up to date with a race through the history of structural biology, from the publication of the first protein structures - myoglobin and haemoglobin - in 1958 to the 100,000th structure that entered the Protein Data Bank in 2014. If you want to read more about the numerous events and publications around the world that honoured and publicised crystallographers during 2014, the best place to start is probably the official website of IYCr2014. And if you have access to Chemistry World, the membership magazine of the Royal Society of Chemistry, you can read two more pieces by me: "Crystal Clear" in the January 2014 issue and "Life in the Freeze Frame", featuring structural biology, in September. (Unfortunately, it is not available in the Birkbeck e-library.)

2014 was designated as the International Year of Crystallography by the United Nations, as part of its programme of using anniversaries to highlight topics and issues that it sees as important. There have been many international years on science-based topics, some broader than others: 2005, for example, was the International Year of Physics. And in this new year the focus moves on to another physical science topic. 2015 is the International Year of Light: or more precisely that "... of Light and Light-based Technologies".

And optics, the science of light, is very closely related to crystallography. Both light and X-rays are parts of the electro-magnetic spectrum and as such are both particles and waves; the differences in their frequencies and wavelengths lead to their very different properties. The first X-ray diffraction experiments were conducted mainly to find out whether the hypothesis that X-rays were electromagnetic waves with a wavelength of about 1 Angstrom was correct. The utility of this technique as a probe for molecular structure was initially a side effect of the similarity between this wavelength and the length of a covalent bond. (So-called "copper K-alpha" radiation, which is often used in crystallography, has a wavelength of 1.54Å, which is exactly equivalent to the length of a single C-C bond.) And the basic equation that defines X-ray diffraction - Bragg's Law, or nλ = 2d sin θ - applies to all electromagnetic radiation, not just to X-rays.

Advances in optical technology have been responsible for some important advances in crystallography. The discovery, in the mid- twentieth century, that charged particles emit electromagnetic radiation in the form of X-rays when accelerated radially was initially viewed as a problem of energy loss. This "lost" radiation, which is orders of magnitude more intense than the X-rays used in the first diffractometers, was soon exploited in synchrotron radiation sources and most non-routine protein structures are now solved using synchrotron radiation. The UK's synchrotron source, a doughnut-shaped structure half a kilometre across located at Harwell in Oxfordshire, is even known officially as "Diamond Light Source". And recent advances in optics are gradually reducing the size of intense X-ray sources so that it will become possible to do complex structural biology that now needs a synchrotron using a lab-based machine.

The next big technical advance to influence X-ray crystallography is the free electron laser, which can generate pulses of X-rays that are much more intense than those produced by even the largest synchrotrons. This is a beam of electrons that is accelerated to almost the speed of light through a side-to-side magnetic field to produce pulses of extremely intense electromagnetic radiation. These pulses are exceptionally short, each lasting only a few femtoseconds (1 fs = 10^-15s). This is a feature of the technology that leads to two advantages: the crystals remain intact, even though they are exposed to extremely intense radiation, and it becomes possible to take "snapshot" structures very close together in time study the dynamic behaviour of molecules. Free electron laser radiation also enables precise structures to be obtained from much smaller crystals, which makes large complexes and membrane-bound proteins more tractable to crystallography. And it may one day be possible, using this technique, to determine a structure from the smallest "crystal" of all - a single molecule - and thus liberate protein crystallography from one of its most important bottlenecks: the need to grow protein crystals.

Acknowledgement:This post owes much to this one on the "Crystallography 365" blog (author unknown)

A Very Short History of Crystallography

You might possibly have been intrigued to read in my last post that 2014 has been designated as the International Year of Crystallography. This year was chosen to celebrate the fact that this discipline - the study of atomic and molecular structure through their crystal forms - is now almost exactly a hundred years old. Admittedly, the first paper in the discipline, rather charmingly titled just "The diffraction of short electro-magnetic waves by a crystal" was published in 1913, and the Nobel Prize awarded two years later, but 2014 is at least a good compromise.

It can be said, perhaps simplistically, that crystallography was invented by the father-and-son team of William Henry and William Lawrence (known as Lawrence) Bragg, at the Universities of Leeds and Cambridge in the UK. The Braggs, however, did not aim to found a new discipline or even to investigate the atomic properties of matter. They were more interested in solving a problem that had been puzzling the cleverest physicists in the world for almost two decades. X-rays had been discovered by Wilhelm Rőntgen in Germany in 1895, but their very name (the unknown X) suggests reveals their controversial nature. Were they particles or waves?

The older Bragg, William, was convinced that X-rays were particles, and set out to prove this to his son (who favoured the wave theory) by exploiting the discovery of another German physicist, von Laue, that X-rays shone at a crystal were scattered and could produce a pattern on a film. Lawrence was the first to realise that these patterns could be explained by the theory that the X-rays were reflected from planes of atoms in the crystal and interfered with each other.

Lawrence presented these results to the Cambridge Philosophical Society late in 1912 and published them in the paper mentioned above the following year. This paper also included the first formulation of one of the best known of all laws of physics: Bragg's Law. This relates the wavelength of incoming X-rays and the angles that they are scattered (diffracted) to the spacing between planes of atoms in a crystal, enabling scientists to determine the geometry of atomic crystal lattices.

The Braggs worked together in Leeds and published their first structures, including that of sodium chloride (common salt) before Lawrence was sent to France to fight in the First World War. He was in the trenches when he heard that he and his father had been awarded the 1915 Nobel Prize for Physics; that news reached him shortly after that of the death of his brother Robert. At only 25, he was (and still remains) the youngest ever recipient of a Nobel Prize.

Technical advances between the wars enabled scientists working in this new discipline to solve the structures of rather more complex molecules. Kathleen Lansdale, one many women who began their research careers as the Braggs' students, solved the structures of benzene derivatives and was the first to see that aromatic rings were flat. And two later developments paved the way for the explosion in structural science that characterised the later twentieth century. In 1934, John Desmond (J.D.) Bernal, who later became the first head of the School of Crystallography at Birkbeck (the predecessor department of our Biological Sciences) and his student Dorothy Crowfoot (later Hodgkin) obtained the first X-ray diffraction patterns from protein crystals. And in the following year Lindo Patterson developed a function that greatly simplified the mathematics involved in structure determination.

Even fifty years ago however, solving crystal structures was a long and at times tedious business. A typical crystallogaphy PhD thesis of the 1960s or 1970s would contain the structures of maybe three small or medium-sized molecules. It is now possible to generate as many in a few hours, so it is possible to see clearly how structures of molecules respond to changes in conditios such as temperature and pressure.

All these discoveries have been made possible by advances in technology, and particularly by the development of synchrotron radiation as a source of powerful beams of X-rays. Synchrotron radiation is produced when charged particles are accelerated radially, and synchrotrons built primarily as X-ray sources were first built in the 1980s. The UK's synchrotron, Diamond at Harwell in Oxfordshire, is currently the fifth largest in the world. It has 23 separate "beamlines", each providing a beam of X-rays with properties that have been optimised for a particular experimental technique.

Synchrotrons provide facilities for solving structures from single crystals of large and small molecules, including, of course, proteins, and from micro-crystalline samples (the latter technique is known as powder diffraction). Although structural biology attracts much of the attention (see almost all the other posts on this blog) structures of smaller molecules can still provide important insights. Sandy Blake, a crystallographer at the University of Nottingham, is using Diamond beamlines to solve the structures of novel materials called metal-organic frameworks or MOFs that are able to store gases including hydrogen (which is a potential fuel source) and greenhouse gases.

At 100, crystallography is still a young discipline but it has radically transformed many other areas of science and, through them, the world we inhabit today. This has been reflected in decisions made by the Nobel committees over the decades. The International Union of Crystallography maintains a list of Nobels awarded for ‘achievements directly related to, or involving the use of, crystallography’. There are now 29 of these, and the latest year with no crystallography-related Nobel was 2008. Even the 2013 Chemistry prize, awarded to Martin Karplus, Michael Levitt and Arieh Warshel, appears on the list: their discipline of computational chemistry would be impossible without structural knowledge obtained through crystallography.

And it almost goes without saying that protein structure, and structural biology more generally - the disciplines taught in this course and its associated MSc - owe their existence to the development of X-ray crystallography.

This blog post is based on an article I wrote for the Royal Society of Chemistry's membership journal, Chemistry World. It will be published in the January 2014 issue of the journal.