First ‘X-ray films’ of moving biomolecules
Great advantages for the development of new medicines
It has been known for fifty years that biomolecules are continually changing shape and that this behaviour is essential for their function. In collaboration with colleagues from America, Utrecht chemists have now succeeded in imaging these changes, which offers great advantages for the development of new medicines. The scientists’ findings were published in the new open access scientific journal eLife on 18 December.
Like all proteins in human body cells, biomolecules are three-dimensional structures that often consist of thousands of atoms. Biomolecules do not have a standard structure, because they continually change shape.
Molecules on film
Up till now, researchers have only been able to take snap-shots of biomolecules in one shape, generally their preferred shape. “So far, we have only been able to say that they did, in fact, change shape. But now, we can actually show at an atomic level how the molecules move and change shape,” explains Dr Tom Burnley of Utrecht University.“We have taken the step from separate three-dimensional snap-shots to a series of shapes. The best thing about this development is that we can make these ‘films’ of each of the 75,000 biomolecules, of which we have captured their preferred shape and entered into the Worldwide Protein Data Bank.”
Development of new medicines
The ‘films’ offer much more information than the individual preferred structures. For instance, the scientists discovered that some of the proteins they researched were very flexible, and not rigid, as is usual, in their interaction with other molecules. Their flexibility is probably necessary for the function of the biomolecules.In capturing the dynamics of biomolecules on film, the scientist have gained more insight into the life processes on a biomolecular level, which incidentally also offers great advantages for the development of new medicines. “We always missed an important part of the puzzle,” explains Prof. Piet Gros, “but now our comprehension of the interaction between a medicine and a biomolecule has greatly improved, which makes the development of potential new medicines more reliable.”
Watch an 'X-ray film'.
Success after 20 years
‘Films’ are made by determining the three-dimensional structure of a protein with X-ray crystallography, which is then combined with computer simulations of molecule movements. The initial problem in the making of these ‘films’ was that the number of variables necessary for the simulation was greater than the number of measuring points provided by crystallography. The chemists were able to solve this problem by separating two movements, individual molecular vibrations and differences in molecule orientation, and modelling them in a clever way.Piet Gros had previously tried to capture the movements of biomolecules in his doctoral research twenty years ago, but did not succeed then. Other researchers failed, too. Gros decided to try it again in 2008, which was made possible by the Spinoza Prize and the ERC Advanced Grant. This time, he succeeded.
Publication
Modelling dynamics in protein crystal structures by ensemble refinement.Burnley BT, Afonine PV, Adams PD, Gros P.
eLife 2012; doi: 10.7554/elife.00311
eLife is an open-access journal for the very best in science backed by the Howard Hughes Medical Institute, the Max Planck Society, and the Wellcome Trust. eLife is online at elife.elifesciences.org.