LINKING BIOMOLECULAR STRUCTURE AND FUNCTION
THROUGH INTEGRATED COMPUTER AND PHYSICAL MODELING
MICHAEL H. PATRICK
Department of Medical Genetics, University of Wisconsin-Madison mpatrick@facstaff.wisc.edu
TIM HERMAN
Center for BioMolecular Modeling, Milwaukee School of Engineering herman@msoe.edu
Understanding biology at the molecular level is, for many students, a daunting challenge because it is abstract and not tangible: they are asked to make inferences about systems with which they have no experience and to provide answers to questions they have never asked. We have developed an inquiry-driven approach to help make the molecular world real and relevant to students, including those whose interest and direction may lie outside the sciences. At the core of this approach is the integrated use of computer visualization software and unique, 3-dimensional physical models of proteins, nucleic acids, and other biomolecules created by stateof-the-art rapid prototyping technologies, based on atomic coordinates of solved structures. These are used to make predictions about structure-function relationships that can be tested experimentally. A multi year research project is in progress to evaluate the efficacy of this approach at the college and pre-college levels.
Going from the observable to the unobservable
Science involves constructing an understanding of something that is unknown; people who become scientists are attracted by that. For many students, however, the study of science can be frustrating and incomprehensible; some may even find it to be a useless exercise utterly irrelevant to their lives. This is exacerbated by the learning mode in many classrooms: short-term memorization of facts…... facts that students fail to connect with fundamental concepts or of how their world works. Indeed, it has been suggested that one of the problems with our educational system is that we reward students for providing answers to questions they have never asked.
The similarity in learning science or doing science is that both involve constructing understanding and new knowledge based on something already known; and, for both, a certain amount of abstraction is involved. Abstract reasoning seems easier, however, if it is based upon past experiences and/or familiar objects or phenomena. Consider for example, the flow of genetic information, from genotype to phenotype, a fundamental concept in biology. This concept is central to understanding the basis for both the continuity and diversity of species and understanding modern biotechnology. At the level of the organism, this flow of genetic information is readily observed and understood through classical means of inferring genotypes from observable traits. In the classroom, there are several outstanding activities using plants, animals, and microbes that promote constructing this empirical understanding. Moreover, structure-function relationships, while sometimes

subtle, are nevertheless directly observable at the level of organisms because the relevant anatomy and physiology is directly observable and comparable among species.
To most students, however, abstraction involving the molecular world is difficult to impossible, because this world is not “real” --- it is not related to things they already know and/or could infer from experience and observation. If it is not “real”, it is not surprising that it seems irrelevant to them– and to many, arcane if not magic. Moreover, it is usually presented in a language – chemistry – in which students are usually not at all fluent. The result is often that connecting molecular structure with function, and therefore understanding what might be called the “molecular logic of life”, does not occur.
This problem is equally serious at both the precollege and the undergraduate levels..
According to a major study conducted by the National Institute for Science Education at
UW-Madison, "Introductory college-level science, mathematics, engineering, and technology courses act as curriculum "pressure points" --- they shape student career trajectories, influence science literacy, and promote equity."[1] One of the problems, however, is that these introductory level courses usually do not connect the science being taught with other sciences or with specific career goals. And in upper level courses, instructors often engage their students in the same laboratory exercises they experienced as undergraduates[2].
Because of the revolution experienced in the biological sciences in the last half of this century, the interface between the biological and the physical sciences has blurred.
Hybrid fields have emerged as biological problems under investigation are studied with thinking and tools that are drawn from chemistry, physics, mathematics and computer science. However, many undergraduate courses in biology do not reflect this change. This is due, in part, to an inadequate background of students in the physical sciences, exacerbated by insufficient connections between biology and the physical sciences. This problem in turn resonates with inadequate learning materials and opportunities for students to interact with them (e.g. laboratories which are not only anachronistic in their content, but also cook-book in their format).
Pedagogical approaches that address some of these problems have been identified by NISE and others [3], including projects funded by the NSF Systemic Chemistry
Initiative [4] They include the use of:
 student-focused active learning
 guided inquiry/open-ended laboratories
 interdisciplinary connections
 topic-oriented approach
 information technology
Molecular structure and function and how we teach it
One of the great epiphanies of 20 th
century science was discovering how a molecule’s function arises from its structure, and realizing how information is conveyed through molecular shape. This is at the core of molecular and cell biology and modern biotechnology. Seeing the 3-dimensional structure of a biological molecule for the first

time can be a revelation for the scientist and the student. The Watson-Crick DNA structure, for example, offers immediate insight into how the molecule copies itself and thus, how heredity works. If, armed with equal insight regarding protein structure, students might more easily appreciate the flow of genetic information at the molecular level, as codified by Francis Crick in his famous Central Dogma: how the information encoded digitally in a one-dimensional chemical array in DNA becomes structural, 3-dimensional information in the form of a protein that carries out some function necessary for life.
At the same time that our understanding of the molecular world has experienced tremendous growth, our methods to bring this understanding to our students has not. For example, we still rely almost entirely on static, two-dimensional drawings of proteins and protein active sites to present this material to students. A survey of popular undergraduate biochemistry texts, for example, reveals many similarities in their treatment of the enzyme lysozyme. Two texts used a well-known drawing of this enzyme with its bound substrate.
In one text, this figure is accompanied by the paragraph [5]:
“The oligosaccarhide sits in a shallow crevice that contains recognizable binding sites for six hexose units. These are labeled
A through F in the figure. All the sites appear to be tailored to bind the acetamide side chains but sites A,C, and E are not spacious enough to accommodate the lactyl group of MurNAc.”
In another textbook, a computer rendering of a space filled" view of lysozyme is shown [6],
"(NAG)3 binds at the enzyme active site by forming five hydrogen bonds with residues located in one-half of a depression or crevice that spans the surface of the enzyme."
While in both cases the text that accompanies these figures is clear, precise and accurate, it is nevertheless unrealistic to think that students can truly appreciate the significance of these statements while viewing these two-dimensional figures.
Modeling molecular structure
Until recently, graphical displays of the type shown above were all that was available. However, new technology now allows this information to be conveyed in a more

exciting and meaningful way. To understand the functional consequences of a three dimensional structure, students must be provided with a three-dimensional model of that structure to analyze. The most readily available model is that generated by various computer graphics programs. Although the image that is created on the computer screen is in fact two-dimensional, various shading, depth cueing and kinetic depth effects can produce an image with takes on three-dimensional character as soon as the user begins to rotate the model on the screen. Although these computer visualization programs were originally developed for UNIX-based computer workstations, public-domain versions of this software now exist that can be downloaded from the Internet and used free of charge
(e.g. RasMol, Protein Explorer, Swiss PDB Viewer). They are powerful programs that will run on any standard desktop computer (PC or Mac).
An even more engaging kind of three-dimensional protein model that can be used to enhance a molecular structure/function curriculum is a physical model. Physical models have several advantages over the computer generated models, especially in the initial phase of a "guided-inquiry approach" in which students are encouraged to think about a molecular structure and formulate questions that they would like to explore further in the laboratory or with the aid of a molecular visualization computer program.
Until recently, physical models of proteins and other molecular structures are not been readily available to educators. However, with the creation of the Center for
BioMolecular Modeling, it is now possible to apply rapid prototyping technology to the production of accurate three-dimensional models of any protein whose structure has been determined (and whose coordinates have been deposited in the Protein Data Bank) can be generated. A variety of different rapid prototyping technologies can be used to construct these models at scales ranging from 0.1 to 1.0 Å per cm, and in several formats (alpha carbon backbone, ball and stick, space-filled, and surface models showing electrostatic potentials). It is also possible to "zoom in" on a small region of a protein to produce an accurate model of the alpha carbon backbone and amino acid side chains that constitute an enzyme active site.
Physical modeling: background
The field of structural biology has enjoyed phenomenal growth and development over the past three decades. By 1970, only 11 protein structures had been solved. These initial structures were of proteins, like hemoglobin, that were easily purified in large amounts, and then conveniently crystallized. Since that time, advances in molecular biology and protein crystallization, along with improvements in computer hardware and software, have transformed this field from a small fraternity of scientists working on a few obscure problems, into a mainstream approach that impacts the work of virtually all biological scientists. The number of protein structures solved during this time has been increasing at an exponential rate, from 15-20 structures per year in the 1980's to approximately 100 per month in 1994. The Protein Data
Bank is projected to contain over 30,000 structures by the year 2004.
The construction of a model representing the electron density of a protein has always been a critical exercise in any protein structure determination. Initially, this was done by tracing electron density contour maps onto thin sheets of Plexiglas that were then stacked up to give the

initial impression of a three-dimensional model. This approach was later refined in the use of a
“Richard’s box”, in which the protein model was constructed from appropriately scaled parts by fitting them into the electron density that was observed through the use of a half-silvered mirror that reflected the model into the density. Still later, a device invented by Byron Rubin (“Byron’s
Bender”) made it possible to bend steel wire into a backbone model of a protein, using the phi/psi angles of each alpha carbon atom
The development in the late 1970's of FRODO, the first software package to generate three-dimensional computer models of proteins from electron density data, eliminated in large part the need for crystallographers to continue the laborious and painstaking job of physical model construction. In subsequent years, these software packages have been enhanced and refined, along with dramatically increased computer power, resulting in the molecular visualization programs briefly described above.
The preceding description of the development of structural biology and molecular visualization over the past 30 years pertains primarily to practicing structural biologists.
However, as structural biology has become a mainstream approach in virtually all the biosciences, a much larger group of biochemists and molecular biologists are now experiencing the need to visualize and analyze these new structures. It is with this later group of biological scientists that physical models are of value. Physical models accurately portray not only the alpha carbon backbone of the protein, but also critical amino acid side chains as well as important bound substrates or inhibitors. The physical model requires neither a molecular graphics workstation nor personnel experienced in using such systems.
Criteria that make physical models appealing to researchers are also ones that make them useful to educators:

First, the physical model is both tactile and interactive. It can be viewed from the top, bottom and side in quick succession, faster than even the most adept computer graphics user. In other words, it is the ideal portable graphical display.

Second, unlike the computer-generated model, the physical model is always “on”.
It is “on” as it sits on the lab bench, where it can be used for impromptu discussions of new experiments, demonstrations to visitors, and to teachers and students who just want to muse and speculate about a molecular structure.
At the same time that structural biology was experiencing a period of rapid growth and development, a similar phenomenon was occurring in an engineering discipline known as Solid
Freeform Fabrication. As in structural biology, new developments in both software and hardware combined to revolutionize this area of manufacturing. Computer-assisted design
(CAD) software was developed to allow engineers to quickly and accurately design three dimensional objects in the computer environment. At the same time, rapid prototyping technologies were developed which used the output from the CAD software packages to drive equipment that rapidly constructed a physical model of the part. Today, five different prototyping technologies are widely used in the design and manufacture of everything from automobile engines to soda bottles and child-proof caps for prescription drug bottles.

How we design and build physical molecular models
All of the available rapid prototyping technologies have been employed in the construction of different molecular models. For more information on the models, the technology and how they are used in research and education, please visit the web site for the Center for
BioMolecular Modeling ( http://www.rpc.msoe.edu/cbm/ ).
Building a model of any molecule requires that their exists a file containing the x-ray crystallographic data that describes the x,y,z coordinates of every atom in the molecule. For molecules whose structure has been determined, these data are stored as pdb files at the Protein
Data Bank, the single worldwide repository for the processing and distribution of 3-D biological macromolecular structure data ( http://nist.rcsb.org/pdb/ )
.
These files are freely accessible for downloading and displaying on any desktop computer using molecular visualization software such as RasMol, Chime, or Protein Explorer, which are also freely available
( http://www.umass.edu/microbio/rasmol/ )
The next step is to convert the pdb file into a “build” file that translates the atomic coordinates into a set of instructions that directs a rapid prototyping machine to create a macroscopic physical model....a kind of computer-assisted design, or CAD, file. This is done in several different ways depending on the type of representation of the structure we wish to model.
Shown below are three RasMol images of the protein, beta globin, each of which can be converted into a physical model:
 a backbone representation, which shows the orientation of the amino acid backbone
(peptide bond-alpha carbon-peptide bond) in space in order to see regions of secondary structure (in this case, alpha helices),
 a stick representation, which adds stick-like representation of all atoms in the backbone and side chains, using CPK coloring, and finally
 a space-filled representation, showing the van der Waals radii of all atoms in the protein.
To make a backbone model, we scale up the atomic dimensions to the macroscopic level and eliminate all atoms but the alpha carbon. We then connect each of these together either by a
“pipe” to make a continuous zig-zig solid structure, the vertices of which are the alpha carbon atoms. The stick model is produced in a similar fashion, with the addition of open-ended pipes representing the atoms of the side chains. Since the usual rapid prototyping machines do not build in color, post-build painting of the models by hand is necessary. Finally, a much differentlooking type of model is created by representing each atom by a sphere proportional to its van

der Waals radius. The result is a “space-fill” model in which any given atom is in contact with several others.
The recent acquisition of a fifth rapid prototyping machine, the Z Corp model 402 color printer allows us to incorporate color directly into the build process. This is the technology used to create the 3D Translation Kit. The models shown in the photos of the Kit not only demonstrate the color, they also show representations different from those described above, using proprietary software designed for the Center for BioMolecular Modeling by Roger Sayles.
For example, instead of representing the backbone as small zig-zag pipes, we can assign an arbitrary radius to the alpha carbon such that the polypeptide backbone is a “string of beads”.
For nucleic acids, a similar operation is carried out by assigning an arbitrary radius to the phosphate in order to create a linear chain of nucleotides.
A somewhat similar-looking model is built by yet a different protoyping technique to create a “surface model”. Here, we use a program that essentially rolls a ball of arbitrary diameter across the entire surface of the molecule. The representation is that of peaks and valleys --- essentially a physical topographic map of the molecule’s surface. We are currently developing software that will color the peaks according to their electrostatic potential, thereby showing where concentrations of positive and negative charges are located.
Ongoing education projects involving our integrated modeling approach
We are currently engaged in two major federally-funded projects directed at the precollege and college level to develop, evaluate and disseminate this approach. A major component of the projects is to connect instructor with researchers, using molecular modeling to bridge the gap between the classroom and the laboratory. The models thus serve dual functions: instructional material in the classroom and thinking tools in the hands of researchers.
For high school teachers, introduction to the approach and subsequent curriculum development takes place in three week intensive summer courses, with follow up workshops. For undergraduate instructors, we have established several individual collaborations in which we meet with the instructors to develop an instructional unit for a course in which modeling is incorporated as an integral part of the instruction. An external evaluation team designs a protocol to assess the efficacy of the modeling in aiding student understanding of molecular structure and function. These courses range from introductory
(freshman and sophomore) courses in biology and chemistry for science majors to advanced courses for majors (e.g. biochemistry) to courses for non-majors.
In each case, a few guiding principles are established:
1. Tying molecular structure with function is a synthesis of fundamental concepts in biology, chemistry, and physics, and it requires establishing and testing models of how we think this world is constructed and operates. But models are just that….models. They represent an attempt to reify something we cannot see, touch, smell, or hear. Scientists rely on extraordinarily clever and sophisticated extensions of all these senses to probe the unseen. But at the end of the day, there is no way to know if the model is correct except the

“test of time”…..and with this, the scrutiny of other scientists. Rarely, if ever, has a model remain unchanged; and rarely, if ever, has only one model sufficed to describe the imagined reality. One of the difficulties faced by teachers is having students think that a single model is reality and then getting them to think in terms of multiple models as a way of understanding what the reality is.
2. The lingua franca for molecular biology is chemistry. Ultimately, we would like our students –even non-majors—to become somewhat conversant with the language since it is the best way to convey essential points accurately. But many students—even science majors at the advanced level—still have difficulty “thinking” in chemistry. So, for each instructor and for each class, there is the initial decision: to explain the molecules and processes in terms of the underlying chemistry, or to let the molecules and processes themselves explain the chemistry. Both approaches are possible. The essential point is to maintain accuracy and rigor.
3. At the precollege and introductory undergraduate level, the microscopic world of molecules MUST be connected to the macroscopic world. That is, the molecule and all that an instructor wishes to have students know about the molecule must EXPLAIN something in the observable “real” world. We illustrate this in our summer courses and workshops by putting the biomolecular modeling within the context of a fundamental biological process. The best developed of these is the unit on circulation, oxygen transport, and the globin protein. The material shown below is taken from the instructional unit which is available on CD from the Center for BioMolecular Modeling.
USING HEMOGLOBIN TO LINK MOLECULAR STRUCTURE AND
FUNCTION AND THE CENTRAL DOGMA
A guide to the content background material, use of integrated computer and physical molecular modeling, and student explorations of basic concepts
PART I: Blood, Hemoglobin, And Oxygen Transport
In this section, we put the unit into perspective by exploring some familiar concepts about oxygen and life with experience and observation (e.g. the red color of blood) through questions such as:

Why is oxygen needed...an overview of where oxidative metabolism fits into the whole scheme of things

What is the simplest way for it to get to where it is needed and what are the limitations; evolution of circulatory systems and a comparative analysis of how plants and animals have solved the transport problems

The nature of blood and blood cells.....

Evolution of oxygen carrier molecules...the convergence on a molecular design; why is a protein needed? why does the protein need to be in a red blood cell?

We also examine why these questions cannot be answered except by understanding some very fundamental principles of chemistry.
PART II: Hemoglobin Structure And Function
The function of hemoglobin is linked to its structure by focusing on one of its components, beta-globin. A series of activities is used to explore primary, secondary sequence, and how a protein folds into a preferred tertiary structure.
Comparison of other globins shows the evolutionary pattern of how nature solved an important problem in terms of molecular design. Included are physical and computer modeling activities.
Laboratory experimentation on the properties of globin and hemoglobin, as well as discussion on the differences between monomeric oxygen storage proteins, such as myoglobin, and the tetrameric oxygen transport protein, hemoglobin, are included
DNA, through the sequence of ribonucleotides that comprise the messenger
RNA , and finally, to a sequence of amino acids that comprise the final betaglobin protein. Along the way, they “discover” things like:

2 strands of DNA.--- which one is used as the template for the synthesis of mRNA?

3 different triplet codon "reading frames".--- which one is used to translate the mRNA into protein?
 split genes.--- why is the globin gene interrupted by two introns?
PART III: The Globin Gene and the Flow of Information
This section begins by extracting DNA, but doing it in such a way that the difference between DNA and proteins is visibly apparent. We do this by using avian red blood cells, which retain their nucleus upon maturation. When these red blood cells are broken open and the resulting cell lysate is subjected to low speed centrifugation, the soluble, red-colored hemoglobin protein remains in the supernatant while the DNA - still contained within the white nuclei - is pelleted to the bottom of the centrifuge tube
Simple but effective ways to tie DNA structure with information are explored by modeling and experimentation. This is followed by a an analysis of the globin gene from its nucleotide sequence is obtained from a database
(GenBank) accessible through the Internet. This exercise allows students to trace the "flow of information" from this sequence of deoxyribonucleotides in

TABLE OF CONTENTS
PART I: BLOOD, HEMOGLOBIN, AND OXYGEN TRANSPORT
A. WHY MUST WE HAVE OXYGEN?
………………………………p.5
1.
to burn fuel for energy needed for life processes:
2. to create order and complexity
B. WHAT IS THE ROLE OF OXYGEN?
…………………….……….p.6
1. Some fundamental chemistry and biochemistry
C. WHY IS A PROTEIN NECESSARY TO CARRY OXYGEN?
.. …p.9
1. Oxygen is not very soluble in water---why
2. What is the mechanism to get oxygen to cells?
3. Oxygen, blood and hemoglobin
PART II: HEMOGLOBIN STRUCTURE AND FUNCTION
A. PROTEINS: WHAT DO WE NEED TO KNOW
…………….……...p.12
1. Proteins are linear, asymmetric polymers
2. Proteins are very large assemblies of different amino acids
3. The structure of proteins and other important biomolecules is based on the chemistry of the carbon atom.
4. Amino acids, linked together, adopt preferred shapes in space .
5. Regions of secondary structure fold up in a very specific way to create the tertiary structure of a functional protein.
B. MODELING HEMOGLOBIN STRUCTURE AND FUNCTION …..p.27
1. Some background information
2 .
Modeling Activities
C. THE REASON BEHIND PROTEIN STRUCTURE ……..……………p.32
1. Strong and weak bonds
2.
Water: the matrix of life
D. SICKLE CELL ANEMIA ………………………..…………………….p.40
1.
2.
Some background
Phenotypic Changes: Microscopic And Macroscopic
3. Classroom resources
E. EXTENSIONS ……………………..………...………………………...p.43
PART III: THE GLOBIN GENE AND THE FLOW OF INFORMATION
A. THE CENTRAL DOGMA AND DNA STRUCTURE/FUNCTION .p.44
1.
What is the Central Dogma and why is it important?
2. Linking DNA structure with its function
B. WATSON, CRICK, AND DNA
………………………………….………….p.48
1. What was measured…what was deduced
2. What the structure explains
3. Modeling DNA
C. GETTING A FEELING FOR DNA …………………………………p.49
1. How big is it? a scaling exercise
2. Extracting DNA from avian erythrocytes
D. DNA AS INFORMATION ………….………………………………..p.53
1. Analyzing the nucleotide sequence encoding the beta-globin protein.
2. Genetic basis for sickle cell anemia
E. EXTENSIONS ………………………………………………………… p.57

APPENDICES………………………………………………………….p.58
The modeling activities used in this unit range from the use of simple, everyday items such as paper clips, beads and string, to the commercial toy, Toobers and Zots. Each of these has great teaching potential but the teacher must also be aware of the misinformation that they provide as well. We move from their to commercially available modeling kits and show that while these are fine to model simple molecules, they do not suffice to model proteins and nucleic acids. For this, we turn to the Construction Kits designed by the
Center for BioMolecular Modeling, which can be seen on their web site. These kits are used in conjunction with RasMol. The same approach is used when we model secondary and tertiary structure and examine why a protein folds that way. This, together with using the Internet databases to compare the same molecule from other species allows us to uncover the essential features of globin that evolved to allow it to function as a an oxygen carrier or storage protein.
Here is an example of a modeling exercise that introduces the concept of protein folding without necessarily having to use chemical vocabulary. We use it as a prelude to actual molecular models.
We can model a protein in many ways; some of these were tried earlier (pipe cleaners, pop-it beads, etc.). The basic point to get across is that a protein is a
(linear, asymmetric) assembly of chemical units called amino acids. There are
20 kinds of amino acids nature uses to make proteins; each has its own properties (charged, uncharged, water-hating, water-loving, etc.) To make a protein, we need some instructions to tell us the sequence of amino acids. We will use the following materials to model a protein:
 a “Toober”, a tube of approximately 1 m in length made from a flexible metal rod sheathed in colorful Styrofoam (made by HandsOn Toys).
 20 different colored tacks (or “Zots”)
For this activity, we will make our protein with just two colored Zots: yellow and blue.
Each learner is given a Toober into which a dozen or so yellow and blue tacks are stuck at constant, measured intervals. Each person has the same number of Zots but each a different sequence. The instructions are that the
“protein” must fold up according to the following rule: imagine that the protein is in water and the yellow Zots are water-hating and the blue Zots are water-loving. Fold the protein up so that the blue Zots are in the water and the yellow Zots aren’t. By and large, they will find that the yellow Zots are on the inside and make as many contact with other yellow Zots as possible. The blue Zots are generally e on the outside. The take home lesson is that the two principles outlined above have been followed to generate as many different 3dimensional structures as there are different sequences. Thus, from simple chemical rules comes an amazing diversity of protein structures……each potentially having a different function (see earlier exercise) and requiring a different set of instructions (i.e.genes).

Building links between education and research communities
In addition to implementing the curriculum in their classrooms, we strongly encourage teachers to form “student design teams”, who identifies a molecule under active investigation in the laboratory of a local biomedical institution. The team, along with their teacher, researches the structure, biological function, and significance of the molecule and design and build the molecule. A seminar for the class on the project is given by the team along with the researcher. So far, this has resulted in the construction of
 a protein synthesis module (including tRNAs, tRNA synthetase, 30S and 50S ribosomal subunits by a team of five Milwaukee teachers in consultation from Tom
Steitz, Harry Noller, and David Goodsell
 a set of the three major proteins involved in anthrax pathogenesis, carried out by a team of Milwaukee high school students in consultation with researchers at UW-
Madison and Univ. Chicago.
Our recent experience with this approach has been very exciting. The approach works because it meets the needs of four key players in the educational landscape:
1.
The research community is very interested in working with teachers and their students in this program because they are not only contributing a valuable outreach program targeted to local schools, but they are also getting a unique and valuable tool in return….a physical model of their protein.
2.
The teachers receive valuable professional development in the area of molecular structure and function….but as a natural by-product of a program that is focused on their students. We have found high school teachers to be incredibly devoted to their students and are willing to go to extraordinary efforts to provide unique and rewarding experiences to them.
3.
The students are exposed not only to concepts of molecular structure and function, but more importantly, to “science in action”. By modeling a protein that is under current investigation in a local research lab, they are brought into contact with the P.I., research associates, post-docs and graduate students who work in the lab. The students experience “science as a process”…….as they meet with the lab to discuss important features of the protein that should be designed into the physical model…..and hear about the ongoing research that is being conducted to better understand how the protein functions.
4.
The school is very supportive of efforts by its teachers to provide a unique extra-curricular experience to their students. These stories of very real “collaborations” between a group of students and a local research lab are of interest to local news media. Media coverage of these stories brings recognition to the school, which will in turn continue to encourage and support the on-going professional development of its teachers.
Summary
Understanding the relationship between a molecular structure and the function it carries out in a cell is the core of what might be called "the molecular logic of the living state". This understanding is often very difficult to achieve for many students because the molecular world is invisible to the unamplified senses. Physical models can play an important role in making this

invisible world "real". These physical models are especially powerful when used in conjunction with computer visualization software and inquiry-based laboratory experiments.
Acknowledgements
This work has been supported by grants from the National Institutes of Health (SEPA;
1R25RR15236-01) and the National Science Foundation (CCLI; DUE-9952693).
We also wish to acknowledge our partners at University of Wisconsin-Madison,
University of Chicago, DePauw University, Carthage College, Lawrence University and Alverno
College who are testing this approach at their institutions. Finally, we extend our grateful appreciation to the work of our project evaluators: Dianne Bowcock and Sharon Schlegel of the
L.E.A.D. Center at UW-Madison, and Eric Hagedorn of the Center for Math and Science
Education Research at UW-Milwaukee.
Bios
MICHAEL PATRICK is Co-Director of the Wisconsin Teacher Enhancement Programs in
Biology at UW-Madison and The Center for BioMolecular Modeling at the Milwaukee School of Engineering. Trained as a biophysicist, he was an NIH-funded researcher at the University of
Texas at Dallas, retiring as Professor of Molecular and Cell Biology. He has been working in science education since 1987 .
TIM HERMAN, is Director of the Center for BioMolecular Modeling at the Milwaukee School of Engineering. He received his doctorate in biochemistry and carried out research in molecular structure/function at the Medical College of Wisconsin until, in 1998, he turned to applying this to science education at the Center for BioMolecular Modeling.
References
[1] See the NISE, College Level One web site: http://www.wcer.wisc.edu/nise/cl1
[2] P.A.Basiliand J.P. Sanford. "Conceptual Change Strategies and Cooperative Group Work in
Chemistry". Journal of Research in Science Teaching. 28 (1991) 293-304
[3] Amer. Chem. Soc. Educational Policies for National Survival. ACS. 1155 Sixteenth Street,
N.W., Washington, C.C. 20201. July 1991
[4] T.R. Lord “A Look A Spatial Abilities In Undergraduate Women Science Majors”.
Journal of Research in Science Teaching . 24 , (1987) 757-767.
[5] G. Zubay, “Biochemistry” Fig.9-30, p.244 3 rd
Ed. (Wm. C. Brown)
[6] L. Stryer, “Biochemistry” Fig. 9-5, p.209 4 th
Ed (Freeman)