DOING CHEMISTRY
IN A VIRTUAL WORLD

VRML, a new web technology, holds promise for chemistry in three dimensions

James H. Krieger

C&EN Washington

Chemists dealing with information on the Internet can't get comfortable with one set of initials these days, it seems, before there are even more to learn. Just when HTML (hypertext markup language) is becoming familiar, along comes VRML (virtual reality modeling language).

VRML (pronounced vermal) holds the promise for chemistry of literally ratcheting up the Internet information revolution to another dimension. VRML is the three-dimensional analog of HTML. And chemistry is inherently three dimensional.

"The hottest VRML application is chemistry," says David Frerichs, VRML product line manager at Silicon Graphics Inc., Mountain View, Calif. "That's something that a lot of people haven't caught on to." Silicon Graphics, a computer manufacturer that has by far the bulk of the workstation market in chemistry, has been leading the VRML development in general as it has taken place over the past several years.

Although activity in VRML development and its chemistry applications have been simmering for more than a year, they may be about to move to a full boil. In August, the VRML development community reached consensus on the standard specification for a new version of VRML - 2.0. That move promises to set off a new round of development activity on applications of VRML, including notably chemistry.

HTML, as the computer-platform-independent method of encoding documents for presentation on the World Wide Web, has been the agent helping to drive the explosive growth of the web for delivery of chemical information. It plays that same role in the rapid expansion of web technology to intranets, as companies and others install the organizationwide networks. But HTML is limited to a two-dimensional world.

A virtue of VRML is that, like HTML, it is platform-independent. It isn't tied to a particular computer environment - PC, Macintosh, UNIX workstation, or whatever. And it is interactive. Furthermore, like HTML, VRML allows for hyperlinking, in this case from points within the 3-D object on a screen to other documents. VRML 2.0 now takes interactivity to an entirely new plane of capability.

VRML 2.0 is one of the things software developers, like those at Tripos Inc., St. Louis, have been looking for, according to Kevin Koboldt, product manager for Tripos' Discovery.Net Club. Tripos is a developer of computational chemistry and molecular modeling software. "We think standards are great," Koboldt says, "because standards are really the only way to extend the device independence that the net is bringing to everybody."

A VRML Scene generated at Imperial College, London, depicting the hydrolysis of dimethyl sulfide shows how atoms and bonds can be hyperlinked to other documents with explanations of their activity.

Tripos developers see VRML as a way to extend that device independence, Koboldt notes. It's important, he says, "not only for developers especially, but also for our users, because the places where our customers are tend to have a mix and match of different kinds of equipment."

David M. Zirl, Silicon Graphics chemistry market manager, notes that VRML is gaining in popularity. "I think it's an important technology," he says. "It lets you look at 3-D objects on the web, which is pretty important. All chemists want to look at molecules in 3-D."

Nevertheless, development of VRML and its applications are as yet at a very early stage and quite distant from mainstream computer-based chemistry. Thomas H. Pierce, a computational chemist at Rohm and Haas, Philadelphia, for example, notes that it is one of the few web technologies that he doesn't program at the moment. "I just read about it and explore," he adds.

Still, Pierce thinks that VRML is going to become important. "It's a trend that's valuable to keep track of and watch as a chemist," he says, "because it could be quite useful and would be an easy way to convert databases into viewable, distributable images."

But chemistry is just one application of VRML - albeit a major one - and the development momentum of the entire world of VRML is building. The adoption of VRML 2.0 as a standard represents a step-change in capability from version 1.0, which had been the standard since this past January. Moreover, a couple of conferences scheduled for early next year will provide further stimulus to the language's evolution and application.

In late January 1997, the World Movers VRML 2.0 Developers Conference is being hosted in San Francisco by Seybold Seminars, a division of Softbank Expos, Foster City, Calif., along with Silicon Graphics; Netscape Communications, Mountain View, Calif.; and Apple Computer, Cupertino, Calif. Seybold Seminars produces events, publications, and web sites dealing with innovative issues and technologies in the publishing industry. Chemistry, in fact, is the focus of one topical area in the presentations at the upcoming World Movers conference.

The San Francisco gathering will be followed a month later in Monterey, Calif., by VRML 97, the 2nd Annual Symposium on VRML. VRML 97 is sponsored by two special-interest groups of ACM, an international scientific and educational organization devoted to computing.

TO SIDEBAR: Encoding in VRML

The World Wide Web, a client-server domain on the Internet, has been growing at an exponential clip, and chemistry has been very much a part of that (C&EN, Sept. 16, page 38). To maneuver around the web, a user employs a browser that interprets files encoded with HTML to provide the content seen on the screen. Among widely used browsers, for example, are Netscape Navigator from Netscape and Internet Explorer from Microsoft, Seattle.

Web content can include documents, graphics, video, and audio files. Browsers are able to interpret certain file formats other than HTML - formats such as GIF (graphics interchange format) and JPEG (joint photographic experts group) for graphics files, for example - to incorporate those files within the browser screen image. But for other formats, the browser employs so-called helper applications - independent programs launched by the browser in separate windows to open those files. More recently, many such programs have been developed as plug-ins for the browsers - programs separate from the browser but which operate within the browser environment to provide integrated content within the browser window.

For chemistry, HTML is a 2-D straitjacket. Hence, even before the advent of VRML, many computer programs designed to display molecular images in 3-D views have been pressed into service as helper applications or plug-ins for web browsers.

One stand-alone program that has been popular as a browser helper application is RasMol, developed by Roger A. Sayle of Glaxo Research & Development, Greenford, England, and downloadable free of charge as a contribution by Glaxo to the chemistry community (available at http://www.umass.edu/microbio/ rasmol/). The program, which can run on a wide range of platforms, displays proteins, nucleic acids, and small molecules based on atomic coordinate files, such as Brookhaven Protein Databank (PDB) files. The images formed are" live," in that they can be magnified and rotated. But only a fixed image can be displayed, one file at a time.

Using RasMol as a jumping off point for its own development, MDL Information Systems Inc. (MDLI), San Leandro, Calif., has more recently introduced a Netscape Navigator plug-in called Chime that is part of its new Chemscape product line. Chime, available free for home and academic use (http://www.mdli. com), displays 3-D structures based on a wide range of formats.

As a plug-in, Chime displays structures directly within an HTML page. It enables users to rotate the structures, but it also allows HTML authors to automatically provide for rotation, with no user intervention. And Chime provides the capability for multiple plug-ins to be run simultaneously, so that, for example, a number of live structures can be included within a table.

Indeed, with such capabilities, Chime is beginning to show up more and more on web sites. One of the most recent, for example, is the site of PCR Custom/Research Chemicals, Gainesville, Fla., a division of Harris Specialty Chemicals (http://www.hsc-ss.com). The company has begun displaying some of its specialty chemicals, such as phenyl dimethicone trimer, using Chime.

Two other products round out the Chemscape line. A commercial product, Chime Pro, has all the features of the basic version of Chime but incorporates the capability of accepting a structure query and in-line data. It thus teams with Chemscape Server, a server system that directly integrates Netscape's Netscape Server with MDLI's ISIS/Host to provide full structure and textual searching from within a web browser.

Among other 3-D molecular viewers that can be used as helper applications is that of Molecular Simulations Inc. (MSI), San Diego, a computational chemistry and molecular modeling software company. Introduced in August, WebLab Viewer is the first in a line of products based on web technology to be introduced by MSI and is designed to be a common web entrée to the company's Cerius² modeling applications. Available for downloading free of charge (http://www.msi.com/weblab), the viewer can turn chemical structures from a wide range of common file formats into high-quality, annotated 3-D images with a wide variety of display styles.

Almost no one expects VRML to displace the 3-D molecular viewers. But although the current 3-D viewers stunningly depict molecules and crystals in three dimensions, they lack certain of VRML's virtues. With version 2.0, those attributes are now beginning to be realized. For chemistry on the web, they could have far-ranging significance in information delivery, research, and education.

VRML stems from ideas generated early in 1994 at the first annual World Wide Web Conference in Geneva and aimed at developing 3-D graphical visualization tools for use on the web. As a 3-D reflection of HTML, VRML began life as an acronym for virtual reality markup language, but that was later changed to virtual reality modeling language to more accurately convey its intended use.

Unlike graphics files in formats such as GIF or JPEG, but like files encoded in HTML, those encoded in VRML consist of plain text (standard ASCII text) that describes a scene. Also, as with HTML, it is the use of plain text for the encoding that makes VRML independent of the computer platform and that enables locations or objects in a scene to be hyperlinked. And since the files are text, which moreover can be transferred in a compressed format and uncompressed automatically by a viewer, VRML files require far less bandwidth for transfer on the Internet than would files in a graphics format.

When a web browser encounters a VRML file, the file is downloaded into the browser. A VRML plug-in viewer for the browser then interprets the VRML file and renders the scene in real time, many times a second. In this way, depending on bandwidth and the capabilities of the client computer, a user can interact more or less smoothly with the scene - manipulate a molecule, say - in real time employing the plug-in viewer's navigation tools.

For example, Netscape has a plug-in viewer for VRML 1.0 called Live3D. It is available from Netscape for Navigator 3.0 and can be downloaded free (http://www.netscape.com).

Following the Geneva conference, a VRML community formed and agreed to push development of a draft specification for the first version of VRML to have ready by that fall. Requirements for the first version were agreed upon, and because of the shortness of time, a search began for an existing solution that could be adapted. After deliberation, the VRML community settled on the Open Inventor ASCII File Format from Silicon Graphics. So VRML 1.0 is based on a subset of the Inventor file format, with extensions to support networking.

TO SIDEBAR: Chlorobenzene encounters VRML

As it happens, Open Inventor spawned another Silicon Graphics program for presenting chemistry in 3-D: Molecular Inventor, a chemistry visualization tool kit that enables scientific professionals to develop and seamlessly share 3-D molecular graphics and associated chemical information between molecular modeling and database software and collaboration tools. The tool kit, released in June, defines a standard 3-D file format for cut-and-paste data exchange between scientific applications, such as molecular modeling, and Silicon Graphics' desktop collaboration environment. Although Molecular Inventor currently runs only on the Silicon Graphics platform, Silicon Graphics has an agreement with a San Diego firm, Template Graphics, that is working on software versions for other UNIX platforms as well as PC platforms.

Back on the VRML-development front, the VRML community decided - in a move to smooth design and implementation of VRML - that except for the hyperlinking feature, VRML 1.0 would not support interactive behaviors. That was left for version 2.0.

In January, a request for proposals for VRML 2.0 went out through the VRML community. A plan called Moving Worlds, created by Silicon Graphics along with Sony Research and a 3-D and Internet information systems consultant named Mitra, was one of six proposals. Inputs to the plan came from others in the VRML community as well, such as Apple Computer. Following debate and arrival at a consensus, the VRML community through a poll eventually selected Moving Worlds as the basis of VRML 2.0.

VRML 2.0 is more than just a simple extension of VRML 1.0 and requires a browser designed for it. But it is the enhancements offered by VRML 2.0 that have created the excitement among software developers. Among them are the following:

• Ability to add sound to a scene - breaking glass or ringing telephones, for example - to enhance realism.
• Ability to encode a scene with various sensors in the software that set off events when certain objects are clicked, that allow a user to drag objects or controls from one place to another, that keep track of the passage of time, or that detect collisions.
• Availability of animation objects called interpolators that make possible the creation of moving objects such as flying birds or automatically opening doors, or objects such as the sun that change color as they move, or objects that morph their geometry from one shape to another.
• Ability to incorporate scripts - batch files with commands written, for example, in JAVA. JAVA is a programming language developed by Sun Microsystems, Mountain View, Calif., for writing small programs, called JAVA applets, to run on the web within a browser.

Scripts allow visual effects to be achieved by means of events. A script takes input from sensors, such as a touch sensor activated by a click with the pointing device on a particular area, and generates events based on that input. The events can change other parts of the VRML world, since they can be passed around among nodes using special statements. As a result, not only can creatures and objects be animated, they can be given a semblance of intelligence. Some examples are the flying birds, or clock hands that can move, dogs that can fetch newspapers, and robots that can juggle.

Not surprisingly, Silicon Graphics has been quick out of the gate with a suite of products aimed at capitalizing on VRML 2.0. Called Cosmo, the suite consists of four products. Cosmo Create, an HTML page layout tool, and Cosmo Worlds, a VRML 2.0-compliant authoring system for developing interactive 3-D worlds, both run on the Silicon Graphics platform. Cosmo Code 2.0, which also runs on the Silicon Graphics platform, is a visual JAVA development environment for creating cross-platform applications. The three programs are priced individually, but all three can be downloaded for $2,500.

Cosmo Player, however, is available for downloading free (http://vrml.sgi.com). It is a VRML 2.0-compliant viewer that works as a plug-in for Netscape Navigator and Microsoft Explorer for multiple platforms, including those using Windows 95 and Windows NT as well as Silicon Graphics. Cosmo Player can display both VRML 1.0 and 2.0 and replaces WebSpace, a workstation web browser previously available from Silicon Graphics. Silicon Graphics' Frerichs notes that the company has distributed some 1.3 million copies of Cosmo Player so far.

"I think you're going to see some very interesting capabilities now, with VRML 2.0 coming out," Frerichs says. For example, he notes, "you're going to be able to see chemical models in VRML where you'll be able to pluck an atom from a molecule and watch it dynamically rearrange itself."

With the ability to interface JAVA applets to the VRML world, Frerichs says, that world can become a true platform for both education and simulation. For example, applications might include on-line computer-based training as well as sharing of information in databases, such as a DNA database.

Noting the limitations of VRML 1.0, Tripos' Koboldt says the version's lack of interactivity meant that all sense of doing chemistry was lost in the viewer. "Now, with VRML 2.0," he says, "you are going to have the ability to tie applets to interactions with the user - in our case, interactions with the chemist. So, when the chemist picks on a bond or a line, we know it's a bond and we can respond in context to the interaction with the chemist."

Koboldt also says that the establishment of a standard for VRML 2.0 is important not only for what it eventually will mean to the users but to the software developers as well. He says one developer he's talked with foresees JAVA libraries supporting graphics primitives, the basic constituents of a scene. By linking to libraries, the developer told him," we'll be able to do rendering, we'll be able to do a lot of things very quickly, without having to write it all ourselves." The developer, Koboldt adds, "thinks that's going to be a natural extension of the language, and it's the last piece in the puzzle that he's sort of waiting for."

For a chemist, says Silicon Graphics' Zirl, VRML "is broadening the scope of people who can look at your models, even broadening the scope within your own company. You're a chemist at a large pharmaceutical company. You want people to know what you did, whether they are people you closely work with on your research team or people who are in your general research community. Maybe it's your manager, or your manager's manager."

If these people can click on their computer screens and see a report that the chemist wrote on some molecule and realize they can rotate the molecule in 3-D, that's important, Zirl suggests. If they can link to a page where the chemist describes the methods used to create the molecule, it's even better, he adds.

"It's sort of laying the infrastructure of the future," Zirl says.

One factor that may act as a governor on the speed of adoption of VRML among users is computer processing speed as the computer hardware now broadly in use catches up with leading-edge hardware technology. That's an observation, for example, by Rohm and Haas's Pierce, who notes the need for graphics image processing power.

And chemistry professor Jürgen Brickmann at the Physical Chemistry Institute at Darmstadt Technical University in Germany, who is one of the pioneers in chemical applications of VRML, points to the bandwidth problem. The Internet becomes extremely slow, particularly in Europe, he notes. Transfer of very complex objects, he says, could take a long period of time.

On the other hand, Brickmann says, there is so much information that cannot be transferred other than by visual representation. From that point of view, he very much likes the VRML idea as an opportunity for chemists to inspect objects as they like to do it. "All these things are a great chance for chemists," he adds.

More specific inklings of what may lie in store for chemistry as a result of VRML can be gathered from the work of some chemists who have been experimenting with the technology for a year or so now. Much of this work has been carried out in Europe.

Brickmann and his coworkers, for instance, have provided examples of VRML applications to chemistry on the Darmstadt web site (http://ws05.pc.chemie. th-darmstadt.de/vrml/). Among the items there is a paper by Brickmann and Darmstadt chemist Horst Vollhardt, "3-D Molecular Graphics on the World Wide Web," prepared for the 1996 Pacific Symposium on Biocomputing held in Hawaii in January. An example of the use of VRML allows users to view the complete cytochrome P450 enzyme or parts of it by switching between different display styles, including wireframe, capped sticks, ball-and-stick, and a CPK space-filling model. The Computer Chemistry Center at the Institute of Organic Chemistry at Friedrich-Alexander University, Erlangen-Nuremberg, Germany, has a VRML conversion service (http:// schiele.organik.uni-erlangen.de/services/ vrml.html). A software program created by Wolf-Dietrich Ihlenfeldt there generates free of charge a VRML molecular image from a SMILES string (a common form of line notation) or a structure file.

Among the earliest pioneering explorations of chemistry applications in VRML have been those of a group of researchers headed by Henry S. Rzepa, a reader in organic chemistry at Imperial College of Science, Technology & Medicine, London. The work derived initially from an EyeChem Chemical Collaboratory project (http://www.ch.ic.ac.uk/ rzepa/CG/CG.html). Several examples illustrate VRML's versatility.

Much of organic chemistry involves recognition of factors that mediate reactivity, Rzepa explains, and one of the most popular methods is to investigate the frontier orbital interactions involved in the reaction. Such interactions, he points out, are often understandable only in a 3-D context. Moreover, there is no widely available cross-platform program for displaying these interactions as there is with ball-and-stick molecular diagrams. In discussing selectivity in the Diels-Alder reaction, Rzepa along with Omer Casher, a researcher in Rzepa's group, and Guillermo A. Suñer of the chemistry department at the University of the Balearic Islands, Palma de Mallorca, Spain, prepared a series of transition-state models encoded in VRML. These contained isosurface representations of frontier orbitals to illustrate the scientific arguments (http://www.ch.ic.ac.uk/ectoc/papers/70/).

In another example, a quantitative assessment was made by David A. Widdowson in the department of chemistry at Imperial College of the lifetime of dimethyl sulfate in blood. The overpowering of an emergency room staff at a general hospital had been ascribed to the release of dimethyl sulfate from a blood sample removed from a patient shortly before the patient died. The molecule hydrolyzes very rapidly in aqueous media, however. To illustrate the atoms and bonds involved in the hydrolytic process, Rzepa and Casher prepared a VRML" scene" of the molecule, with all the key atoms and bonds hyperlinked to further explanations of their activity. The VRML document is a companion piece to Widdowson's analysis (http://www.ch.ic.ac. uk/equinox/dmso4.wrl).

As a third example, some 1,300 significantly different molecules were contributed to the Electronic Conference on Heterocyclic Chemistry (ECHET96) held on the web from late June to late July, a joint collaboration between Rzepa, the International Society for Heterocyclic Chemistry, and the Royal Society of Chemistry. One way to analyze such a molecule collection is to perform various similarity tests and to present the results as aesthetics-based graph layout (AGLO) diagrams. These 3-D diagrams can show nearest-neighbor interactions between features such as molecular centers identified for each paper submitted to the conference. Interested readers could thus browse the conference in a quite novel manner, Rzepa points out. The AGLO diagrams were encoded in VRML (http://lead.ch.ic.ac.uk:8000/gwtalk2/ aglo.html), and the work, carried out by Christopher Leach, will be submitted for publication shortly.

Where VRML will go with chemistry and its ultimate impact on the presentation of chemistry on the web is, of course, still to be seen. But with the introduction of VRML 2.0, and presumably further extensions in later versions, the technology's capabilities would seem enough to set any chemist's imagination turning.

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