Structural Biology
The building blocks of DNA direct the synthesis of proteins, whose shape and structure will be determined by neutron scattering at SNS and HFIR.
Understanding how proteins work is a key to unlocking the secrets of life. As enzymes, proteins catalyze a living cell’s chemistry. As hormones, they regulate the body’s development and direct the activities of its organs. Proteins defend us against infection, but in their mutant forms or as coats on viruses, they contribute to the development of diseases, such as cancer and AIDS. The key to making proteins diverse and specific in their functions is the intricate shape each type of molecule takes (ranging from ellipsoids to saucers to dumbbells).
Neutrons provide information that complements that obtained by x-rays on nearly microscopic protein crystals. Experiments show that such crystals can be grown larger than 1 cubic millimeter on an orbiting space station to form a sufficient number of molecular units for a meaningful neutron analysis. Also, neutrons complement x-rays in studies of proteins in solution, which could be of vital interest to the pharmaceutical, agricultural, and biotechnology industries.
The superior ability of neutrons to precisely locate hydrogen (or deuterium) atoms-as well as carbon, oxygen, nitrogen, and phosphorus atoms-in macromolecular structures is important in the search to learn more about proteins. Knowing the structure of proteins is essential for designing drugs to block a protein that is causing disorder.
Neutrons are useful for studying mechanisms of enzyme activity (e.g., how the enzymatic process changes a substrate or how a drug blocks the function of the enzyme). In studies of a deuterated substrate bound to an enzyme, neutrons can help scientists determine the location of the enzyme’s active site and the probability that a potential drug will bind to that site and block the enzyme’s undesired activity.
Neutrons are playing a significant role in studies of macromolecular structure.
Using neutron scattering to determine the structure of body enzymes will aid the development of more effective therapeutic drugs.
The power of neutron scattering to detect hydrogen atoms is shown in this image of hydrated carbon monoxide myoglobin. The space-filling stippled structures on the protein stick model are hydrating water molecules.
Neutrons are also useful for studying protein folding-the process by which a string of amino acids folds reproducibly to yield the protein’s functional three-dimensional shape. One way that folding affects function is by bringing together widely separated amino acids to form an active site-the catalytic region of an enzyme where binding with a biochemical substance (substrate) occurs. Only neutrons can allow scientists to "see" the critical hydrogen atoms of the active site.
If the protein folding problem could be solved, gene sequences could be translated directly into three-dimensional structures. However, an extraordinary amount of neutron and x-ray data must be generated to aid the long-term development and validation of computer algorithms to predict protein folding. Meanwhile, the structure of almost every interesting protein will require a separate analysis, extending the time required to determine form and function in all macromolecules of biological interest.
The Human Genome Sequencing Project will provide a complete DNA blueprint for the order of chemical bases in the approximately 100,000 genes that code for the 100,000 enzymes, hormones, and structural proteins of human life. The next phase of this project will be to identify these macromolecules and study them to determine their form and function. Aging and cancer are caused partly by the abnormal functioning of DNA and the proteins involved in regulating expression of a person's genetic pattern. Knowing the individual structures of these macromolecules will aid understanding of the chemical nature of disease at the atomic level, as well as the chemical mechanisms of genetic regulation.
