Chemistry for molecular structure.

The Royal Swedish Academy of Sciences has awarded a Nobel Prize for the tenth time for work using X-ray crystallography to determine the structure of molecules. This year's winners in chemistry were honored not for working out a particular structure but for constructing a system of mathematical equations, about 35 years ago, that has greatly facilitated analysis of the position of atoms in crystals of a wide variety of organic and inorganic materials.

The originators of this "direct method" for structure determination are Jerome Karle of the U.S. Naval Research Laboratory in Washington, D.C., and Herbert A. Hauptman, formely of the Naval Research Laboratory and now at the Medical Foundation of Buffalo (N.Y.)

X-ray crystallography "revolutionized" inorganic chemistry and supported "important progress" in natural product chemistry, the nobel award states. It explains, "In order to understand the nature of chemical bonds, the function of molecules in biological contexts and the mechanism and dynamics of reactions, knowledge of the exact molecular structure is absolutely essential."

The structures of thousands of compounds have been described using this technique, Karle told reporters at a press conferenc at conference at the Pentagon. Whereas a single structure formerly took years to determine, now the direct method and modern computers routinely allow chemists to work out a structure in a day or two.

Structures that have been analyzed by the Hauptman-Karle method include hormones, vitamins, antibiotics, potential anticancer drugs and plant-growth promoters. Among compounds of particular interest to the department of Defense are new propellants, which may be used for rockets, and potential antimalarial drugs.

The analytical method of Hauptman and Karle was controversial for more than 10 years after it was first published in 1949, and came into wide use only in the middle 1960s. "Initially it was hard for people to believe that the mathematics would, even in principle, do what it does," Karle says.

When an X-ray beam strikes a crystal, the rays are deflected, primarily by the electrons in the material, in a manner that produces spots of different intensities on a photographic film, Hauptman and Karle devised mathematical equations to describe these spots and to deduce from their intensities the location of atoms in the crystal.

This analysis rests primarily on two conditions, the Nobel award states. First, in a crystal, the electron density is never less than zero. Second, the number of measurements possible is much greater than the number of unknown values in the equations to be sovled. Solving many equations, each "only statistically probable," makes the determinations more reliable.

The Swedish Academy cites several scientists instrumental in the practical application of the method, including Karle's wife, Isabel Karle, also of the Naval Research Laboratory. "We work together separately," Isabel Karle says. "He does the theory. I do the experiments."

The current method is applicable only to relatively small molecules. According to Isabel Karle, the largest molecule so far analyzed by the direct method is the nervous system peptide, enkephalin, which consists of five amino acids and contains 230 carbon, nitrogen and oxygen atoms.

Both Hauptman and Karle are working on new mathematical methods to determine more easily with X-ray crystallography the structures of large molecules, such as proteins, and even such complex entities as viruses.