DIANA PHILLIPS MAHONEY
Atoms and molecules never looked so good, thanks to a novel visualization technique developed at NASA Ames Research Center. Called EVolVis, for electronic volume visualizer, the software lets scientists see atomic and molecular structures and interactions in a way never before possible by computing and visualizing the mathematical properties of the electrical charge distributions of the structures.
The tool addresses one of the major drawbacks of existing molecular visualization approaches, says Preston MacDougall, a chemistry professor at Middle Tennessee State University and collaborator on the research project with NASA Ames visualization expert Chris Henze. The majority of current techniques, he says, "do not visualize atoms in molecules with dutiful attention to the fact that real atoms interact with each other quantum mechanically."
For example, many of the rule-based molecular visualization algorithms rely on an averaging approach to approximate distinctive features in a dataset. Unfortunately, says MacDougall, "the molecular interactions that are the least understood are those that are described as weak and noncovalent." Such interactions are often averaged into non-existence using current methods. In contrast, EVolVis lets users identify and explore subtle interactions-the "lumps and holes" most approaches miss, says MacDougall-by focusing on local concentrations of electron density rather than properties derived from global integration.
Volume rendering the topology of local electron charge densities helps researchers understand how atoms interact with each other quantum mechanically. In this image, EVolVis was used to render methyl fluoride and methyl lithium, polar extremes among small organic molecules. The fluorine atom above the "angelic" image (far left) of methyl fluoride is rich in structure, while the lithium atom (near left, top) has been stripped down to its core. Unconventional hydrogen bonding sites are seen at the extremities of the fluorinated molecule. The property being considered maps regions of local charge concentration and local charge depletion in a molecule. This property is called the Laplacian of the total electronic charge density. By unveiling the topology of the Laplacian specifically, EVolVis uncovers variations that characterize reactive sites in molecules-information that is then visualized for interactive exploration.
The software relies on volume-based rather than surface rendering techniques, which means that users can probe entire molecules without obstruction by opaque surfaces and without having to preselect specific views or layers. The information attained from such a holistic perspective provides critical clues into molecular behavior, including why molecules take their distinctive shapes, how they orient themselves for chemical reactions, and even where new atoms may bind if a molecule is bent out of shape.
The interactive capability is critical, says MacDougall, because it allows scientists an unmatched capability for mining the molecular data for potentially important reactive sites and then focusing on those sites for closer inspection. Most existing tools require the user to pre-select areas they believe might be of interest for investigation. This raises a number of problems, not the least of which is that sometimes what is most interesting is least predictable, thus a scientist might not intuitively know where to target. As a result, important information could easily be overlooked. "Since chemists are busy inventing molecules that have never existed before, as well as copying nature's handiwork, often we want to find and characterize reactive sites that are quite different from anything that we have characterized before," says MacDougall. This can best happen, he says, when the scientist has freedom of movement inside, outside, and all around a complete molecular dataset.
Written in C++ using OpenGL and XWindows, EVolVis can use either electron charge densities computed from wave functions or data obtained through X-ray crystallography to identify reactive sites in a molecule. The results are volume rendered using a 3D texture mapping approach in which the Laplacian data is loaded into 3D texture memory. The volume of data is then sliced perpendicular to the viewer, and the slices are drawn and composited in back-to-front order. A user-controlled transfer function maps the volumetric data onto color and opacity values. By adjusting the transfer function, the user can highlight one or several value ranges in the data to get various types of representations, including isosurfaces, interval volumes, and translucent windows in the data of interest.
The real power of EVolVis, says MacDougall, comes from its opacity transfer function editor. The editor includes slider controls for a range of variables, such as amplitude, offset, variance, and decay rate. "Because the function editing and rendering is interactive, the user can rely on visual feedback to tune the transfer function and bring various data features into and out of focus." For example, he says, "in cases where one wishes to determine relative reactivities of similar atoms, the transfer function can be tuned for that purpose."
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| The lumps and holes sculpted by natural forces at the atomic level of a water molecule are volume rendered using EVolVis (top). The focus in this view is on the central oxygen atom. Another view of topological features within a water molecule (bottom) use |
The new visualization technique has already led to an enhanced understanding of the mechanism and geometry of hydrogen bonding. In visualizing the Laplacian topologies at conventional hydrogen bonding donor sites, the researchers saw unique skullcap-shaped features, which they refer to as yarmulkes. "We found the yarmulkes literally by playing with EvolVis," says MacDougall. Prior to the discovery, he says, "no one knew that a hydrogen bond had any kind of site associated with it. The rule was that a hydrogen was simply a potential donor if it was bonded to a nitrogen, oxygen, or fluorine, and it is generally 'painted' accordingly using conventional biomolecular modeling tools."
The size of the yarmulkes appears to correlate with the varying hydrogen bonding capacities of different sites, says MacDougall. "We also found the yarmulkes near hydrogens that are bonded to certain types of carbon atoms, but not most carbon atoms."
The ability to visualize the numerous and diverse reactive sites that make the chemistry of even seemingly simple molecules complex makes EVolVis particularly appealing for pharmaceutical research. For example, says MacDougall, "each molecule of [the cancer drug] cisplatin has only nine atoms, yet the way it selectively binds to strands of DNA makes it one of the most widely used drugs to fight cancer. If any of the four atoms connected to the molecule's central platinum atom are changed, its efficacy is diminished." The ability to understand such behavior is invaluable to the development of new drugs.
Research into EVolVis and its applications is ongoing. Currently, MacDougall is in the process of seeking additional grants to support further development. Not surprisingly, a number of pharmaceutical researchers have expressed interest.