Software That 'Shakes And Bakes' Molecular Solutions Available Commercially

BUFFALO, N.Y. -- A software program that has solved in hours or minutes molecular structures so complex that other methods could not solve them is now available commercially.

Developed by researchers at the University at Buffalo and the Hauptman-Woodward Medical Research Institute here, Shake-and-Bake -- dubbed SnB -- has been incorporated into teXsan, a software package manufactured by Molecular Structure Corp. that is one of the most widely-used software packages for solving the structures of small and medium-sized molecules.

"SnB takes a whole different approach to solving structures," said Beverly Vincent, Ph.D., small molecule crystallography manager at Molecular Structure Corp. "It works where other approaches fail."

The software package is the first to solve routinely structures of more than 100 atoms and up to 400 atoms when high-quality X-ray diffraction data are available.

"SnB has been able to solve structures that other software packages have been unable to solve," said Russ Miller, Ph.D., UB associate professor of computer science, senior research scientist at the Hauptman-Woodward Medical Research Institute (HWI) and a member of the research team that developed SnB. "So far, it has solved every structure presented to it."

SnB is expected to accelerate profoundly the use of rational drug design, which is the design of new drugs based on precise knowledge of structures of biological molecules.

Recently, HWI researchers have used it to solve 7-ketocholesterol, an oxidized cholesterol structure implicated in atherosclerosis.

"These oxidized cholesterol molecules damage the arterial cell lining and start the formation of plaque, a first step in the progression of atherosclerosis," explained Mary P. McCourt, Ph.D., research scientist at HWI and professor of chemistry at D'Youville College who conducted the work with Doug Dorset, Ph.D., senior research scientist at HWI. "In order to develop strategies for preventing that damage, it's critical that we understand the molecule's structure and function."

McCourt noted that while lipid structures are very difficult to solve, SnB was able to solve 7-ketocholesterol with barely any user input.

"Right away, SnB gave us excellent starting models," she said. "It means there's one less stumbling block to solving complicated structures."

Just four years ago, the Shake-and-Bake method was little more than an idea conceived by Nobel Laureate Herbert Hauptman, Ph.D., president of the Hauptman-Woodward Medical Research Institute and UB research professor of computer science.

He shared the Nobel Prize in chemistry in 1985 with Jerome Karle of the Naval Research Laboratory for their development years earlier of the direct method that allows for the routine determination of molecular structures containing up to 100 nonhydrogen atoms.

Hauptman's idea for the minimal principle, on which the program is based, originated in an elegant, 18th century mathematical principle formulated by mathematician Carl Friedrich Gauss about the orbits of asteroids.

Initially successful when it ran on massively parallel computers, the SnB program was then continually refined and adapted by Miller and Charles M. Weeks, Ph.D., senior research scientist at Hauptman-Woodward.

SnB now solves complex molecules on a standard computer workstation.

According to its developers, the key virtue of the software lies in its ability to solve complex structures with virtually no user assistance.

"Shake-and-Bake solves molecular structures like a black box, with no human intervention, given data with sufficient resolution," said Hauptman. "Scientists should be able to get an answer just by collecting X-ray diffraction data on a molecule and running it on the computer."

Miller explained that existing software packages work well in determining simple, relatively small structures.

"But suppose a structure is larger or complex, or that traditional packages are having difficulty in solving it," he said. "That's when one should invoke SnB. Based on everything we currently know about SnB, it should solve virtually any structure for which reasonable data are available."

Information on how to purchase SnB is available through the World Wide Web at URL http://www.hwi.buffalo.edu/SnB, or by contacting Molecular Structure Corp. at 713-363-1033.

Researchers at institutions that do not have access to teXsan or the World Wide Web may contact Russ Miller or Charles M. Weeks at (716) 856-9600.