AIDS Research

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AIDS Research

Since 1985 the National Aeronautics and Space Administration (NASA) has supported fundamental studies on the various factors that affect protein crystal growth processes. More than thirty principal investigators from universities throughout the United States have investigated questions such as why crystals stop growing, what factors cause defect formations in growing crystals, and what influence parameters such as protein purity, temperature, pH (a solution's degree of acid or base properties), protein concentration, and fluid flows exert around growing crystals.

The majority of these studies were conducted in Earth-based laboratories, with a limited number of experiments performed on U.S. space shuttle flights. The purpose of the space experiments is to determine the effect that a microgravity environment has on the ultimate size and quality of protein crystals. This research was propelled by the need to improve success rates in producing high-quality crystals to be used for X-ray crystallography structure determinations. X-ray crystallography involves exposing a protein crystal to powerful X-ray radiation. When this occurs, the crystal produces a pattern of diffracted spots that can be used to mathematically determine (using computers) the structure of the protein (i.e., the positions of all the atoms that comprise the protein molecule).

Structure-Based Drug Design

The three-dimensional structure of a protein is useful because it helps scientists understand the protein's function in biological systems. In addition, most known diseases are based on proteins that are not working properly within the human body or on foreign proteins that enter the body as part of harmful bacteria, viruses, or other pathogens. The three-dimensional structure of these disease-related proteins can aid scientists in designing new pharmaceutical agents (drugs) that specifically interact with the protein, thereby alleviating or lessening the harmful effects of the associated diseases.

This method of designing new and more effective pharmaceuticals, known as structure-based drug design, was used to develop many of the new-generation AIDS drugs. These drugs were developed using Earth-grown crystals. There are, however, a number of other protein targets in the HIV virus as well as in most other pathogens that have yet to be crystallized. Attempts to grow crystals large enough and of sufficient quality are often unsuccessful, thereby preventing the use of structure-based drug design.

On Earth, when crystals begin to grow, lighter molecules float upward in the protein solution while heavier molecules are pulled down by gravity's forces (a process known as buoyancy-induced fluid flow). This flow of solution causes the protein to be swept to the surface of the crystal where it must align in a very perfect arrangement with other protein molecules. It is believed that the rapid flow of solution causes the protein molecules to become trapped in misalignments, thereby affecting the quality of the crystal and, eventually, even terminating crystal growth.

Crystal Growth in Microgravity

In a microgravity environment, these harmful flows are nonexistent because gravity's influence is minimal.^* Thus, the movement of protein molecules in microgravity is much slower, caused only by a process known as random diffusion (the inherent vibration of individual molecules). It is believed that the lack of buoyancy-induced fluid flows (as occurs on Earth) creates a more quiescent environment for growing crystals. The protein molecules have sufficient time to become more perfectly ordered in the crystal before being trapped by additional incoming molecules.

The scientific community is divided about the role that microgravity can play in improving the size and quality of protein crystals. In addition, the excessive cost of performing experiments in space has caused scientists to question the value of these experiments. Proponents of the space protein crystal growth program are optimistic that the longer growth times that will be available on the International Space Station will significantly improve microgravity success rates for producing crystals of significantly higher quality.

see also Careers in Space Medicine (volume 1); Crystal Growth (volume 3); Microgravity (volume 2); Zero Gravity (volume 3).

Lawrence J. DeLucas