Looking at molecules using X-ray vision

Physicians order X-rays taken when they want to see what’s wrong inside you. Dentists do the same to see what’s wrong with your teeth or to see what’s happening underneath your gums. From X-ray pictures, doctors can tell if a particular part of your body is normal, or if it is diseased. X-rays have become a routine diagnostic tool because they penetrate tissues and reveal, in clear contrast, your various organs. And, of course, X-rays are used in airports and high-security installations to reveal what is inside your luggage, briefcase, wallet, shopping bag, etc.

(And then there is that Superhero who has X-ray vision and can see through cars and buildings and other objects – except those made of lead.)

But X-rays have other uses. For example, we can actually look at atoms and molecules using X-rays. This is because X-rays have short wavelengths.

X-rays, like visible light, are electromagnetic waves. Like all waves, X-rays are regular undulations of crests and valleys. Like all waves, X-rays are characterized by their speed (X-rays and visible light travel at the same speed), wavelength (the distance between successive crests), and amplitude (how high the crests are). The wavelengths associated with X-rays are about one ten-billionth of a meter – very short indeed. Now, the separation between the atoms in a molecule are about that distance, so that X-rays have just the right wavelength to enable us to look at molecules in atomic detail (the shorter the wavelength, the more detail is seen).

So X-rays have become a routine tool to study the structure of molecules, to compare the structures of normal molecules and those which malfunction, to study how molecules work, and so on.

Being electromagnetic waves, X-rays interact with electrical charges (e.g., electrons). Since the different elements have different numbers of electrons, we could distinguish the various atoms in a molecule from each other – if the X-ray picture has enough precision. The picture becomes more precise if the molecules are arranged in a regular array – as in a crystal.

Hundreds of thousands of molecules have been studied by X-ray crystallography, from simple salts (the very first structure studied was that of NaCl) to viruses (with molecular weights in the millions). And, of course, it was from X-ray photographs that Watson and Crick deduced the basic structure of DNA.

One could argue that the molecules in a crystal are far from being in their normal biological or physiological state. True. Yet, it has been shown in many instances that the molecules in a crystal can bind their specific ligand (in the case of receptors), or catalyze their specific reactions (in the case of enzymes), etc. In other words, the molecules in a crystal could display normal function, suggesting that their structure in the crystal is the same as, or is very similar to, their structure under physiological conditions. The first person to demonstrate this was a Filipino, Florante Quiocho, in the 1960s when he was still a graduate student at Yale.

And the many structures that have become available from X-ray crystallography are being put to good use. For example, one drug that has been found to be effective in the treatment of AIDS is a molecule that inhibits the action of a protease that the AIDS virus needs to replicate itself; that inhibitor was designed by closely examining the structure of the protease. For another, the modifications done on the structure of antibodies in order to make them more effective in therapy are made possible by the detailed structures available for those molecules. Indeed, the engineering of proteins – a whole new field in itself – cannot be possible without the protein structures obtained using X-rays or other means.

Protein structures are usually deposited in the Protein Data Bank. For many years, when it was housed at the Brookhaven National Laboratories, the Protein Data Bank was managed by, again, a Filipino, Enrique Abola.

There is an ongoing effort to determine the structure of at least a third of all the proteins that human beings produce. It is felt – and rightfully so – that we need to know the structure if we are to understand the function, as well as the interactions, of the many molecules in our body. Most of the structure analyses will be done using X-rays. Enrique Abola is involved in this effort.

Incidentally, aside from Florante Quiocho and Enrique Abola (and his twin, Jaime), there are other Filipinos, in the Philippines and abroad, who look at molecules using X-rays.

So, step aside Superman. You are not the only one with X-ray vision.

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Eduardo A. Padlan trained in protein crystallography for his Ph.D. He has worked on various proteins, principally on antibodies and other molecules of the immune system. He retired from the US National Institutes of Health in 2000 and is currently an adjunct professor in the Marine Science Institute, College of Science, University of the Philippines Diliman. He is a corresponding member of the National Academy of Science and Technology, Philippines. He can be reached at [email protected]