Molecular Modeling Aids Chemistry Research and Teaching

Author: Franklin Hoke, pp.18 Since full-featured molecular-modeling packages began appearing on the chemist's desktop a few years ago, they have grown dramatically in sophistication and capability. Following in part on the availability of ever-more-powerful personal computer hardware, new software modules have been added regularly, often ported from workstation environments. At the same time, intuitive graphical user interfaces have helped make computer-aided chemistry increasingly accessible to scientists who are not primarily programmers. The following companies are among those providing molecular drawing and modeling software for personal computer operating systems. Because options and modules vary in some cases, call for specific pricing information. Autodesk Inc. Scientific Modeling Division 2320 Marinship Way Sausalito, Calif. 94965 (800) 424-9737 Fax: (415) 331-8093 PC Product: HyperChem (Windows) CAChe Scientific Inc. P.O. Box 500, M/S 13-400 Beaverton, Ore. 97077 (800) 547-8949 Fax: (503) 526-2901 PC Product: Personal CAChe (Macintosh) Cambridge Scientific Computing Inc. 875 Mass. Ave., Sixth Fl. Cambridge, Mass. 02139 (617) 491-6862 Fax: (617) 491-8208 PC Products: CSC ChemDraw, CSC Chem3D, and SC ChemFinder (Macintosh) Molecular Arts Corp. 1532 E. Katella Ave. Anaheim, Calif. 92805 (714) 634-8100 Fax: (714) 634-1999 PC Product: chemDIAGRAM (Windows) Molecular Design Ltd. 14600 Catalina St. San Leandro, Calif. 94577 (510) 895-1313 Fax: (510) 352-2870 PC Product: ISIS/Draw (Macintosh, Windows) SoftShell International Ltd. 715 Horizon Dr., Suite 390 Grand Junction, Colo. 81506 (303) 242-7502 Fax: (303) 242-6469 PC Products: ChemIntosh (Macintosh), ChemWindow (Windows) Tripos Associates Inc. 1699 S. Hanley Rd., Suite 303 St. Louis, Mo. 63144 (800) 323-2960 Fax: (314) 647-9241 PC Products: Alchemy III (Macintosh, DOS, Windows), ChemPrint (Windows) Workstation systems: BIOSYM Technologies Inc. 9685 Scranton Rd. San Diego, Calif. 92121 (619) 458-9990 Fax: (619) 458-0136 Product: Insight II Molecular Simulations Inc. 16 New England Exec. Pk. Burlington, Mass. 01803-5297 (617) 229-9800 Fax: (617) 229-9899 Product: QUANTA CHARMm Tripos Associates Inc. (address above) Product: SYBYL The result is that bench-level experimental chemists and molecular biologists now are designing molecules with the aplomb of computational chemists, and academic chemists are as likely to use the programs for teaching their students as for advancing their research. Many scientists are also using these packages to create information-dense images for textbooks and papers. "The computational chemist--or theoretical chemist--works primarily with computers, the algorithms and so on, and with the theories of chemistry," explains Joanne Hart, a chemist and product marketing specialist with CAChe Scientific Inc., Beaverton, Ore., producers of a suite of Macintosh-based computer-aided chemistry packages. "These are the people writing a lot of the programs that we use now. And then there's the experimental chemist. He's the fellow who's in the lab trying to come up with a new paint, a new fragrance, or a way to make his dye bluer. Our customer is the experimental chemist." In terms of functionality, these modeling systems are situated between personal computer molecular-drawing packages, which are generally less sophisticated, and the full-scale molecular simulation systems designed to run on workstations. In some cases, there is overlap. For example, some drawing packages offer a degree of analytical capability and may have software bridges written into the program to allow them to communicate with more powerful systems. Similarly, some of the personal computer molecular-modeling systems also provide software links to the more powerful workstation packages or are part of a family of software running on the full range of computer platforms. Among the personal computer molecular-modeling systems are Alchemy III (Macintosh, DOS, and Windows) from Tripos Associates Inc., St. Louis; Personal CAChe (Macintosh) from CAChe Scientific; CSC Chem3D (Macintosh) from Cambridge Scientific Computing Inc., Cambridge, Mass.; and HyperChem (Windows) from Autodesk Inc., Sausalito, Calif. All four have software links to workstation capability. Alchemy III is produced by Tripos Associates, which also markets SYBYL, one of the three most widely used workstation molecular-modeling systems. (The other two are Insight II from BIOSYM Technologies Inc. of San Diego, and QUANTA CHARMm from Molecular Simulations Inc., Burlington, Mass.) Personal CAChe, for desktop Macintosh computers, is the first product on an upgrade path that includes CAChe Worksystem, CAChe Groupserver, and CAChe Project Leader. CSC Chem3D exchanges files in a wide range of formats, including those of several workstation modeling packages and a number of important databases, such as the Brookhaven Protein Database and the Cambridge Crystal Database. HyperChem, too, can read and write files back and forth with high-end modeling packages through industry-standard formats, and a version of the program runs under the Motif graphical user interface on RISC-based workstations from Silicon Graphics Inc., Mountain View, Calif. Drawing packages include chemDIAGRAM (Win- dows) from Molecular Arts Corp., Anaheim, Calif.; CSC ChemDraw (Macintosh and Windows) from Cam- bridge Scientific Computing; ChemIntosh (Macintosh) and ChemWindow (Windows) from SoftShell International Ltd., Grand Junction, Colo.; ISIS/ Draw (Macintosh and Windows) from Molecular Design Ltd., San Leandro, Calif.; and ChemPrint (Windows) from Tripos Associates. The drawing packages also demonstrate the bridges software developers have created between the different types of software. Structures drawn in CSC ChemDraw, for example, can be transferred into CSC Chem3D for molecular modeling. Another program in the Cambridge Scientific group, CSC ChemFinder, provides database searching tools--of both structure and information databases -- that integrate with either the drawing or the modeling package. And Molecular Design's ISIS/Draw structures are fully compatible with the company's three-dimensional chemical-structure database search software. Overall, personal computer molecular-modeling tools are opening new research approaches and encouraging interactions between the computer-oriented theoretical chemists and their bench-level counterparts. "Products like HyperChem are positioned to let people do sophisticated molecular modeling without being a dedicated molecular modeler," says Susan Spencer, a marketing representative for Autodesk Inc. "They have to know chemistry, but they don't have to know molecular modeling." Kate M. Holloway is a computational chemist at Merck Research Laboratories, West Point, Pa., and one of the organizers of an upcoming American Chemical Society meeting session (to be held in March 1994, in San Diego) titled "Applications of Computer-Aided Molecular Design to Chemicals, Materials, and Pharmaceuticals." She agrees that academic scientists and bench-level chemists are the most likely users of the personal computer molecular-modeling programs. "These systems have all the functionality that you'd want for simple molecular modeling," Holloway says. "The [workstation] packages from Molecular Simulations and BIOSYM and Tripos are intended for people who are going to be looking at fairly large systems or are interested in specific [capabilities] like solvation calculations, molecular dynamics, Monte Carlo, 3-D pharmacophore building, and database searching. Some of those pieces are present in the smaller packages, but you just don't have the quite the same sophistication or power." In the context of specific investigations, a wide range of analytical tasks can be performed by the personal computer molecular-modeling programs, including geometry minimizations, assessments of electrostatic interactions, and calculations of infrared-, ultraviolet-, and visible-wavelength spectra. What limitations there are--generally in the maximum size of the molecules that can be studied and the speed with which analytical functions on those molecules can be performed--seem to be related more to the hardware than to the software. Stefan Loren, a postdoctoral organic chemist working in the lab of Joel Hawkins at the University of California, Berkeley, is designing a variety of catalysts for asymmetric synthesis of chiral, or racemic, drug molecules with the aid of the CAChe system. These molecules exist in two structural forms that are mirror images of each other, although they conform to the same chemical formula. The right-handed and left-handed versions of such molecules often have very different properties, so that the ability to make one rather than the other is important to drug developers, Loren says. One of the common uses of the program, he says, is to minimize the geometry of a given molecule, looking for different conformations in which the molecule is likely to reside. "From there, one can make predictions about where it might be attacked and what the selectivity might be," Loren says. In addition to the work with chiral molecules, Loren and colleagues have used the workstation version of CAChe to model carbon 60 molecules, or buckminsterfullerenes. Sharon Bryant, a biologist with the National Institute of Environmental Health Sciences' Laboratory of Integrative Biology in Research Triangle Park, N.C., uses Hyper-Chem to visualize opioid peptides in binding situations, investigating receptor sites. Among the analyses she performs are electrostatic calculations, energy minimizations, and infrared-, ultraviolet-, and visible- wavelength spectroscopic studies. Working with molecules as large as 132 atoms, Bryant has tested the limits of her desktop system. For one set of especially demanding semi-empirical calculations she asked the program to do, she ran out of computer memory after five days. The program itself, however, was not the limiting factor. "Also, I could have selected a couple of residues, calculated those, and then gone back to select others," she says. "I could then have combined the data to overcome the memory problem." One point Bryant makes is that her lab added molecular modeling to its set of tools, not to take the place of other techniques, but to do something not easily done otherwise. "We wanted to visualize the peptides," she says, "to understand the molecules." One of the fastest-growing areas of use for personal computer molecular modeling is in teaching. The immediacy of being able to see images of the molecules, combined with the scientific rigor underlying the programming, makes the programs strong interactive learning tools. "I teach a laboratory course where the students spend half their time working in the lab and half their time in front of the computer," says John Kotz, Distinguished Teaching Professor of chemistry at the State University of New York, Oneonta, and a CAChe user. He notes that this time budget is similar to what the students would experience if they were working in an industrial laboratory today. "On the computer, they build the compounds they're going to work on in the lab," Kotz says. "After working in the lab, they follow up by coming back to the computer, to see if the computer matches up with their real experience." He adds: "CAChe allows you to probe the reactivity of the molecule by studying its electronic structure, so you can get some idea of where the electron density is the greatest or the least, and therefore where the molecule is most likely to be attacked." In a chemistry theory course that Kotz also teaches, the computer screen has virtually replaced the blackboard. "We actually teach the class in front of the computer," he says. "Every time we sit down at the computer--and this includes myself--we find things we never thought of before." Kotz is currently at work on the third edition of a freshman chemistry textbook (Kotz and Keith F. Purcell, Chemistry and Chemical Reactivity, 2d ed., Philadelphia, Saunders College `Publishing, 1991) and plans to include a compact disk "hyper- book" containing CAChe-generated chemical structures to augment the book. "You simply browse around inside it," he says. "You can connect from place to place electronically, rather than by turning pages. It's not meant to be page-turned."

Molecular Modeling Aids Chemistry Research and Teaching

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