Crystals, Crystals Everywhere!

A large fraction of all solid materials, both natural and man-made, occur in the crystalline form.  Crystalline materials have long-range order, with their atoms or molecules forming a regular, repetitive, gridlike pattern throughout the material.  Many of these are polycrystalline, that is, they are made up of many single crystals (called grains).  Most metals, alloys and composite materials fall into this category.

However, a significant number of solid materials exist as single crystals.  Single crystals include those in everyday use (e.g. salt and sugar crystals), those used for decorative purposes (e.g. gemstones), and those used in electro-optical devices (e.g. infrared crystals such as zinc selenide and silicon crystals in computer chips).  Crystals of proteins, nucleic acids, viruses and other biological macromolecules are also single crystals.

Why Crystallize Proteins?

The crystallization of proteins currently has three major applications: (1) structural biology and drug design, (2) bioseparations, and (3) controlled drug delivery.  In the first application, the protein crystals are used with the techniques of protein crystallography (see below) to ascertain the three-dimensional structure of the molecule.  This structure is indispensable for correctly determining the often complex biological functions of these macromolecules.  The design of drugs is related to this, and involves designing a molecule that can exactly fit into a binding site of a macromolecule and block its function in the desease pathway.  Producing better quality crystals will result in more accurate 3D protein structures, which in turn means its biological function can be known more precisely, also resulting in improved drug design.

Bioseparations refers to the downstream processing of the products of fermentation.  Typically the desired product of the fermentation process is a protein (e.g. insulin), which then needs to be separated from the biomass.  Crystallization is one of the commonly employed techniques for separating the protein.  It has the advantage of being a benign separations process, that is, it does not cause the protein to unfold and lose its activity.  The issues here are better prediction and control of the crystallization process to facilitate improved design of crystallization units.

The latest application of protein crystals is as a means of achieving controlled drug delivery.  Most drugs are cleared by the body rapidly following administration, making it difficult to achieve a constant desired level over a period of time.  When the drug is a protein (such as insulin or alpha-interferon), administering the drug in the crystalline form shows promise of achieving such controlled delivery and clinical trials are already underway to test it.  The challenge here is to produce crystals of relatively uniform sizes so that the dosage can be prescribed correctly.

Macromolecular Crystallography

Crystallography is the science concerned with the study of crystals.  Modern crystallography is intimately linked with the ability of crystals to diffract X-rays.  The resulting diffraction profile can be used to determine the structure of the crystal, as well as the 3D molecular structure of the crystalline material.  The ability to know the precise molecular structure of biological macromolecules has revolutionized the study of their functions in many fields of biology.

The three-dimensional molecular structure of the protein Hen Egg White Lysozyme.

Protein Crystallization in Space!

The microgravity environment aboard spacecraft in low Earth orbits provides a convection and sedimentation free environment for the study and applications of fluid-based systems.  With the advent of the Space Shuttle, scientists had regular access to such environments and many experiments were initiated, including those in protein crystallization.  After many trials it became clear that for several proteins, crystallization in a microgravity environment resulted in bigger and better quality crystals.  In some instances, crystals that could not be crystallized on the ground at all were found to crystallize in space.  Conversely, for numerous proteins the space environment was found to be no better or was worse than ground-based conditions.

Crystals of Satellite Tobacco Mosaic Virus (STMV) grown on the Space Shuttle mission IML-1 in 1991.  Some of the crystals produced, such as the large one in the figure, were bigger and diffracted to a higher resolution than any produced on the ground.

As a result of these observations, NASA has become one of the leading federal agencies in promoting and funding protein crystallization research.  Efforts are directed at both utilizing the space environment to improve the crystallization of novel proteins and in fundamental investigations of the causes (if any) of the improvement in protein crystals produced in this environment.

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Macromolecular Crystallization Laboratory	Chemical & Environmental Engineering	UT College of Engineering	The University of Toledo