Nano
Scientists from Imperial College London working in collaboration with the University of Surrey have developed a new method to make crystals of proteins, using ‘smart materials’ that remember the shape and characteristics of the protein. This discovery holds great promise for the future development of new drugs.
nucleant’– a substance that could be used to start the successful crystallization of any protein. Finding such a nucleant would be a huge breakthrough for medical science. Chayen, who had previously made
advances in this field by introducing porous materials as nucleating agents, has recently developed a more effective method for making proteins crystallise using materials called ‘molecularly imprinted polymers’, or MIPs. The first step towards the use of these
materials as nucleants occurred back in 2001; the idea was that the pores in the material would trap the protein molecules and encourage them to come together and form a nucleus, which would then grow into a crystal. The principle was proved but a suitable material was not found. The next breakthrough came in 2004
Smart Materials herald a new era of drug design
The process of creating a new drug typically begins with the identification of a protein that is involved in a specific disease. Molecules are then designed that will interact with the protein to either stimulate or block its function, but to do this in a rational way (rather than by trial and error) the structure of the targeted protein must first be ascertained. A technique called X-ray crystallography - which is reliant on high quality crystals - is used for this purpose, but getting a protein to come out of solution and form a crystal poses a major bottleneck to progress. “Proteins are very comfortable in solution,” says Professor Naomi Chayen of the Department of Surgery and Cancer at Imperial College London, “and they need to be convinced to come out and form a crystal.” Finding crystallization conditions for a
new protein can be a close-to-Herculean task. The standard way of obtaining crystals
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is first to screen a wide range of potential chemical mixtures, in order to find ‘hits’ or ‘leads’ that point to conditions that may be conducive to crystallization. Once a lead is identified, optimisation can be performed by fine-tuning crystallization conditions such as the concentration of protein, type and concentration of precipitant, pH, temperature and the addition of additives. However, even after all of this, only around 20% of proteins produce useful crystals, with the rest stuck in a research cul-de-sac.
A Universal Nucleant Nucleation,
the initial process of crystal
formation in which the first few molecules join together, is a crucial step that determines the entire crystallization process. Thus, the ability to control crystal nucleation
would tackle the protein
crystallization problem at its conception. There is an ongoing search for a ‘universal
when Chayen enlisted the help of Professor Larry Hench, a fellow Imperial College scientist, to supply her with bio-glass that was originally used as a scaffold for enabling bone to grow around it. “I realised that this concept could be translated into my line of work, and so I phoned him up and asked if he could make me bio-glass on a nano scale,” says Chayen. This
technique yielded unprecedented
success with many more proteins than ever before. Imperial patented the technology and it was commercialised by an SME company called Molecular Dimensions Ltd, who named the product‘ Naomi’s nucleant’. For
this innovation,
Prof. Chayen was awarded a Women of Outstanding Achievement for Innovation and Entrepreneurship commendation at the WISE (Women in Science and Engineering) awards in 2012.
Personalised Polymers At this point it was clear that porous materials were effective as nucleants, but despite this success, Chayen and her team continued the search. “Our next task was to create pores that had specific affinity to proteins.” This is the point at which MIPs were first
considered. MIPs are compounds (polymers) made up of small units of acrylamide (or other monomers) that bind together, i.e. polymerise, around the outside of a molecule. When the molecule
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