Using Computer-based Molecular Graphics in a Science Course for Non-Majors By Trace Jordan, Neville Kallenbach, and Marvin Rich trace.jordan@nyu.edu; neville.kallenbach@nyu.edu; marvin.rich@nyu.edu

This article is based on a presentation at the April 2001 Teaching More Effectively with Technology conference at NYU. Development of the course materials and website was supported in part by awards from the Special Grants Program, the Camille and Henry Dreyfus Foundation, and by the National Science Foundation's program in Course, Curriculum, and Laboratory Improvement.

Effective science education for undergraduate students who are not specializing in the scientific disciplines continues to be a widespread goal in our nation's colleges and universities. At NYU there has been an unusually strong commitment to this endeavor. When the Morse Academic Plan--NYU's undergraduate core curriculum--was established in 1995, it included an innovative, three-course sequence in mathematics and science for non-majors. This sequence, called the Foundations of Scientific Inquiry (FSI), consists of three courses: Quantitative Reasoning (mathematics), Natural Science I (physical sciences) and Natural Science II (life sciences). Each of the course offerings in the FSI program has a weekly workshop or laboratory where students engage in the process of mathematical reasoning or experimental scientific investigations. A central objective of the faculty who design and teach these courses is to prepare NYU graduates to make informed personal and social decisions in a world that is becoming increasingly influenced by scientific and technological advances.

The FSI program now offers a wide range of courses, each of which focuses on a general theme in mathematics and science. For example, one of the Quantitative Reasoning courses is entitled "Mathematics and the Computer", in which students explore the mathematical principles of computer operation. In the laboratory projects for this course, students begin working with simple switches to implement Boolean operations and progress to designing their own circuits using logic gates on chips. Our range of Natural Science I courses, which focus on the physical sciences, includes "Einstein's Universe", "The Cosmos and the Earth", "Explorations of Light and Color", and "Energy and the Environment". Finally, our life science offerings under the Natural Science II rubric range from courses on neuroscience ("Brain and Behavior"), through physical anthropology ("Human Origins"), to an exploration of ecology and its recent perturbation by humans ("Lessons from the Biosphere").

One of the most exciting areas of modern science is our ever-increasing understanding of how the body works on a molecular level in both health and disease. This is a truly interdisciplinary undertaking, involving scientists from such diverse fields as physics, chemistry, cell biology, and computer science. Our fascination with revealing the molecular machinery of our bodies is accompanied by a practical desire to understand--and hopefully cure--the multiple diseases that currently afflict our society, such as AIDS, cancer, Alzheimer's disease, and many others.

The design of therapeutic drugs over the past century has mostly been a hit-or-miss affair. Some successful drugs have been discovered by serendipity, others by mimicking a natural product from plants, and yet others by a massive program of screening thousands of related molecules for biological activity. Yet we are now on the cusp of an exciting breakthrough: rational drug design. This process involves first understanding the precise structure of a therapeutic target--such as an enzyme in a critical biochemical pathway or the receptor on the surface of a cell--and then designing a drug molecule that will block its action. Rational drug design, it is hoped, will enable scientists to accelerate the speed of drug discovery and create new pharmaceuticals with fewer side effects.

Until now, structural information about biomolecules has been notoriously difficult to obtain, but improvements in techniques and advances in automation have made the process more tractable. There are two primary techniques that are used. The first is X-ray crystallography, where scientists use X-rays to probe the arrangement of atoms in a biological molecule while it is fixed in a crystalline lattice.

The second is nuclear magnetic resonance, a newer experimental technique in which a solution of protein is suspended inside an intense magnet. The spins from all the atomic nuclei in the biomolecule then interact with the magnetic field, thereby allowing scientists (after a painstaking deciphering process) to locate the position of each atom in space.

Once the data are obtained, scientists employ molecular graphics programs to display the structure on a computer and scrutinize the region where the key biological function occurs. For example, enzymes facilitate biochemical reactions in our cells by binding their target molecules to a region called the active site. If we can find an artificial molecule of the perfect size, structure and chemical composition to fit into this active site, this molecule will act as an inhibitor and the enzyme will be rendered inactive.

This is the basic principle of rational drug design. The recent explosion of information now available from the human genome sequence adds further impetus and resources to the search for novel therapeutic pharmaceuticals.

Since one of the goals of the FSI program is to introduce non-science students to important areas of current scientific research, we thought that biomolecular structure and function would be an ideal topic for a new course. The outcome was "The Molecules of Life", a new offering within the Natural Science II suite of courses. This course was jointly designed by Dr. Trace Jordan, Assistant Director of the Morse Academic Plan, and Dr. Neville Kallenbach, Professor in the Department of Chemistry at NYU. They co-taught the course for the first time in the Spring 2001 semester and it will be offered again in the coming academic year. Since we wished to integrate educational technology into the course, Marvin Rich joined the course team as an applications and website programmer.

One of the objectives for this course was to provide students with an opportunity to actively explore the structure of biological molecules, ranging from small amino acids to very large proteins. Since professional researchers use molecular graphics for such investigations, we wanted to see if it were possible to adapt this tool for non-science undergraduates. There were two primary challenges, one technical and one educational. The technical difficulty involved finding a suitable software package that was relatively easy for students to use, not prohibitively expensive, and suitable for implementation on personal computers. Only five years ago this would have been an insurmountable obstacle, since the only molecular graphics programs then available cost thousands of dollars and ran only on large, expensive, UNIX-based workstations. Recently, however, thanks to a group of dedicated scientists and programmers, software has become available that has a large range of features for displaying and manipulating molecular structures. These software packages--called Rasmol and CHIME--can be downloaded for free and function very well on a PC. An illustration of the range of applications for these programs, together with links to download the software, can be obtained through the Rasmol homepage at www.umass.edu/microbio/rasmol/.

The educational challenge involved developing suitable instructional exercises in computer-based molecular graphics that would be appropriate for an introductory course for non-specialists. The use of Rasmol and/or CHIME for teaching biomolecular science had been mostly employed in upper-level courses in biochemistry for science majors. For these courses, it is common to present the biomolecular structures with minimal explication, since the expectation is that students will use them as a self-guided educational tool. While this approach works for science majors who are more advanced in their education, it is completely inappropriate for our course in the FSI program. We therefore developed a series of interactive "instructional modules" for students to work through, accompanied by question-based assignments and performed in course laboratory sessions under the guidance of a graduate student teaching assistant. These instructional modules included: "Introduction to Using the CHIME Software"; "Principles of Molecular Structure"; "Functional Groups in Molecules"; "Principles of Protein Architecture"; and "Enzyme Function and Inhibition".

Figure 1. An image from a course instructional module on HIV protease inhibitors. The HIV protease enzyme is shown as a ribbon diagram, with the protease inhibitor drug bound tightly in its active site. The boxes and text at the right-hand side allow students to explore the structure interactively by highlighting specific features.

One of the images from the course website is shown in Figure 1. It illustrates one of the recent successes of rational drug design: the development of HIV protease inhTraibitors. The HIV protease enzyme is shown as a ribbon structure, which is a schematic representation of the arrangement of its many atoms. The enzyme has a critical role in the lifecycle of HIV within our cells, acting to cut long protein chains into smaller ones so that the virus can assemble new copies of itself. Scientists determined the structure of the enzyme via X-ray crystallography, including the precise location and geometrical arrangement of the active site. Based on this information, they designed drug molecules that were specifically tailored to fit into the active site and inhibit the enzyme's function. One of these "protease inhibitors"--made by Merck Pharmaceuticals--is shown in the figure. While this picture can only give a static view of the enzyme and the drug molecule, the CHIME program allows students to rotate the molecular complex to study its overall structure and highlight particular features using the clickable boxes. By performing the interactive exercises, they gain a deeper appreciation of biomolecular structure and the principles of rational drug design.

These instructional modules using CHIME provide a new instructional methodology for the "Molecules of Life" course. They allow us to teach students about molecular structure, enzyme function, and drug design using an interactive pedagogy that simply would not be possible without the use of computer-assisted instruction. We have extensively evaluated student feedback from the Spring 2001 semester and find that the computer exercises are well-received and valued by the students in the class. We are currently working on improving our existing modules for the laboratory projects and adding new modules to accompany lecture topics. Biomolecular science and rational drug design continue to advance at a rapid pace, and we look forward to sharing these exciting developments with our students in semesters to come.

Address correspondence about this article to Trace Jordan at 100 Washington Square East, Room 903. Phone: 998-8078. E-mail: trace.jordan@nyu.edu. Materials discussed in this article are presented on the course website at: www.nyu.edu/pages/mathmol/molecules/.