Crystal mapping helps battle deadly diseases
molecules is set to revolutionise drug discovery by allowing the
molecular structures of proteins to be studied in greater detail
advancing on the technique of protein crystallography.
The technique, which involves sending beams of neutrons through crystals at freezing temperatures, just a few degrees above 'absolute zero', will for the first time allow scientists to see complete structures of protein molecules, down to the last atom.
The process, Ultra-Cold Neutron Protein Crystallography, improves on current methods by probing protein structures with neutrons at temperatures of 15K (-258 degrees C), dramatically increasing the number of visible atoms. The process especially reveals the hydrogen atoms, which hold the key to many chemical reactions, and because of their low mass, are rarely revealed by current methods like X-Ray Crystallography even if carried out at freezing temperatures.
Current protein crystallization techniques include hanging drop vapour diVusion (HDVD) and sitting drop vapour diVusion (SDVD), which is commonly used with robotic nanodrop setups. Despite the respectable progress made in this sector, tasks remain difficult in feedback from crystal image analysis as well as validation and ligand binding.
Currently, detecting every atom in a protein's molecular structure is not possible. In determining 3D structures of proteins the more information a researcher has, the more he is able to tailor drugs to target specific proteins. An example is with interfering with the function of such proteins in infectious agents like tuberculosis.
An additional example of the technique's power is its ability to show a complete picture of atoms in the protein-binding site for the drug, including the protein's hydrogen and bound water hydrogen molecules (as deuteriums) as well as a correct description of the electric charge details.
Commenting on the technique's main drawback, Professor John Helliwell, lead researcher told DrugResearcher.com: "The technique will essentially cost more. The beam time at current prices is similar per 8-hour shift as synchrotron X-ray time."
"A neutron experiment at present takes longer by a major factor, (approx 100 times). However, new neutron sources being built will change that by a similar factor making the price competitive."
The technique essentially makes other classes of experiments on proteins feasible. In particular, the comparison of protein structures at ultra-cold versus room temperature allows atomic vibration detail to be separated from structural disorders.
Helliwell added that the computational modelling could now have full protein surface relief and electric charge known experimentally.
"With the current neutron sources and the new ones being built there is no reason why such details cannot be available as a matter of routine in the future. The use of two temperatures is more of a special case but offers in addition the details of the dynamics, i.e mobilities of the important binding atoms," he commented.
Helliwell added: "Another research benefit that now becomes possible is chemical reactions can be set running directly in the crystal and then freeze-trapped so as to probe the proteins in time with the neutron beam whilst the protein is actually in its functional state."
The pharmaceutical industry has already taken an interest in this technique with GlaxosmithKline (GSK) involved in a project collaboration, combining the X-ray and neutron approach of the current study with a study of one of GSK's main protein drug targets.
Helliwell's team, which is part of the international linked groups to expand and improve the current instruments provision, including UK, Europe, USA and Japan, now plan to extend their protein research, which involves this technique.
