Activities, simulations, and
computer-modeling programs
that help students visualize
how proteins work.
I
magine a microscopic world filled with tiny Christine Hunter
The protein structure unit presents new probmotors, ratchets, switches, and pumps conlems to students who have learned about engitrolled by complex signaling and feedback systems. Now
neering through structural or mechanical challenges, such as
imagine that these parts can assemble themselves. This is the
bridges, mousetrap cars, or egg drops. It also draws in stuworld we present to students in the protein structure unit of
dents interested in the life sciences who might not consider
our genetic engineering course. Students learn how protein
a typical engineering course. We hope the course makes cell
folding gives rise to the molecular machines in our cells and
biology less abstract for both types of students. This article
how misfolding can lead to disease. Students also explore
describes a series of hands-on activities, online simulations,
how scientists use the engineering design process to treat
and computer-modeling programs that help students visualthese diseases using rational drug design.
ize protein structure and better understand protein function.
February 2015
49
Review of protein synthesis
The students in our course have completed (or are currently enrolled in) one year of high school biology. They have
covered the basic steps of transcription and translation, but
many still find the process confusing. For example, students
tend to conflate transcription and DNA replication, because
both involve copying a DNA template. In addition, many
have memorized the definitions of silent mutation (one that
does not significantly alter the phenotype of the organism)
or frameshift mutation (insertions or deletions in DNA that
change the reading frame and typically result in a non-functional protein) but have difficulty connecting the change in
DNA sequence to the effect on protein function.
As the course begins, students review transcription and
translation by working at Molecular Workbench (see “On
the web”), a website with free interactive simulations in biology, chemistry, and physics in which the teacher can select
activities and track students’ progress. For this unit, the activities DNA to Protein (transcription and translation), Intermolecular Interactions (polar interactions and hydrogen
bonds), and Protein Folding (hydrophobic and hydrophilic
interactions) provide a foundation for the work on protein
design. Students like Molecular Workbench because they can
individually work through each topic at their own pace, and
they receive immediate feedback as they answer questions.
50
The Science Teacher
Protein folding and structure-function
Once students have a firm foundation in DNA transcription and translation and understand protein synthesis, we
discuss the levels of protein structure and the intermolecular
and intramolecular forces that promote folding. Working in
groups of two or three, students model protein folding using
foam Mini-Toobers to represent the protein backbone and
different-colored thumbtacks to represent amino acids (see
“On the web”). Students are asked to create a random linear sequence of “amino acids” on the foam “backbone” and
then fold the protein into a three-dimensional structure such
that hydrophilic amino acids are on the surface (where they
would be exposed to water) and hydrophobic amino acids are
on the inside. They also try to maximize the ionic and disulfide bonds that can form between side chains. This allows
students to observe how a few simple rules allow a linear sequence of amino acids to fold into a three-dimensional structure. They can also compare structures to see that changing
the order of the amino acids changes the resulting shape of
the protein. A similar activity can be done using pipe cleaners
or foam-wrapped garden wire (White 2006; Tempsick 2011).
This activity also introduces structure-function, the idea
that the three-dimensional structure of a protein dictates the
protein’s function. The class brainstorms the ways in which
the structure of a simple tool, such as scissors, is important
Modeling Molecular Machinery
FI G U R E 1
Connecting to the standards.
Foldit Project.
Protein Structure-Function Project
Next Generation Science Standards
Engineering
HS-ETS1 Engineering Design
Life Sciences
HS-LS1 From Molecules to Organisms: Structures and
Processes
Performance Expectation
The materials/lessons/activities outlined in this article
are just one step toward reaching the Performance
Expectations listed below. Additional supporting
materials/lessons/activities will be required.
Performance Expectation
HS-LS1-1: Construct an explanation based on evidence
for how the structure of DNA determines the structure
of proteins which carry out the essential functions of
life through systems of specialized cells.
HS-ETS1-4: Use a computer simulation to model the
impact of proposed solutions to a complex realworld problem with numerous criteria and constraints
on interactions within and between systems relevant to
the problem.
Scientific and Engineering Practice
Constructing Explanations and Designing Solutions:
Construct an explanation based on valid and reliable
evidence obtained from a variety of sources (including
students’ own investigations, models, theories,
simulations, peer review). (HS-LS1-1)
Scientific and Engineering Practice
Using Mathematics and Computational Thinking: Use
mathematical models and/or computer simulations to
predict the effects of a design solution on systems and/
or the interactions between systems. (HS-ETS1-4)
Disciplinary Core Idea
ETS1.B: Developing Possible Solutions: Both physical
models and computers can be used in various ways
to aid in the engineering design process. Computers
are useful for a variety of purposes, such as running
simulations to test different ways of solving a problem
or to see which one is most efficient or economical; and
in making a persuasive presentation to a client about
how a given design will meet his or her needs.
(HS-ETS1-4)
Crosscutting Concept
HS-ETS1-4: Systems and System Models: Models (e.g.,
physical, mathematical, computer models) can be used
to simulate systems and interactions—including energy,
matter, and information flows—within and between
systems at different scales. (HS-ETS1-4)
for the function of the tool. For example, the shape of the
handle allows interaction with the thumb and fingers (similar to a binding site). The blades squeeze together to cut paper (active site), and the hinge allows the blades to open and
close (conformational change). By altering the structure of a
Disciplinary Core Idea
LS1.A: Structure and Function
All cells contain genetic information in the form of DNA
molecules. Genes are regions in the DNA that contain
the instructions that code for the formation of proteins,
which carry out most of the work of cells. (HS-LS1-1)
Crosscutting Concept
Structure and Function: Investigating or designing new
systems or structures requires a detailed examination of
the properties of different materials, the structures of
different components, and connections of components
to reveal its function and/or solve a problem. (HS-LS1-1)
Common Core State Standard
Literacy Standard WHST.9-12.2
Write informative/explanatory texts, including the
narration of historical events, scientific procedures/
experiments, or technical processes.
tool, we can alter its function. For example, left-handed scissors have an altered “binding site” and, in safety scissors or
pinking shears, the “active site” is modified. In the same way,
genetic engineering can be used to alter the function of a protein by changing its shape.
February 2015
51
FI G U R E 2
Student handout for the Protein Structure-Function Project.
Protein Structure-Function Project
This project will give you the chance to apply what
you have learned about protein structure to a protein
of your choice. You will present this research in poster
form at Science Night. Begin by thinking about an area
of biology that interests you and then identify a protein
that plays a role in that process. I would be happy to
help you brainstorm. You might also start by browsing
these sites:
Protopedia (http://bit.ly/1yvuyaT)
PDB (http://bit.ly/1w6dqua)
Create a poster that contains the following
information:
Part I: Background Information
• What is the function of the protein?
• Where is it active (what organism, what cell type)?
• Why is it interesting and important?
Part II: Structural Information
• What is the secondary structure of the protein?
• Describe at least two specific examples of forces that
are important for the tertiary structure (hydrogen
bonding, hydrophobic interactions, disulfide bonds)
• What is the quaternary structure of the protein? Are
there multiple subunits? Are they all the same?
Part III: Interactions
• What naturally occurring molecules interact with
your protein?
• Are there drugs that have been designed to interact
We then move to a simple molecular example of structure-function: prions and other amyloid proteins. These are
a wonderful introduction because of their small size, simple
structure, and terrifying mutant phenotypes. In their properly folded form, prions have a secondary structure that is
mostly alpha-helical, and they play a role in brain development (Costandi 2013). However, the same protein can also
misfold into a beta-sheet structure forming long fibrils that
lead to brain degeneration. This change in shape leads directly to the change in function that causes the devastating
symptoms of diseases such as bovine spongiform encephalopathy (BSE, or mad-cow disease). Start with a short news clip
(see “On the web”) or video about a devastating prion disease
(BSE, kuru, Creutzfeldt-Jakob, or fatal familial insomnia).
Students then read articles on the connection between prion
52
The Science Teacher
with your protein? What are they? What diseases
could they treat?
• What parts of the protein structure are important for
these interactions?
Part IV: Protein Function
• How does the structure of your protein allow it to
carry out its unique function?
• Describe one mutation (not a nonsense mutation)
that affects the function of your protein. How does
it alter the structure of your protein?
• Does your protein have any potential applications to
medicine, industry, etc.?
Pictures
Your poster should include at least four pictures that
illustrate specific aspects of the structure that you have
chosen to discuss. For example, you might include a
ribbon diagram of the secondary structure, a picture
of subunits interacting, a close-up of a ligand binding
site, and a view of a site affected by a mutation.
These pictures should be generated by you using the
molecular visualization software on the PDB site. Do not
paste in pictures obtained from other sources.
References
All sources of information should be cited. Please
review the class handout on “Avoiding Plagiarism in the
Sciences” and ask questions if you are ever uncertain
about your work.
protein structure and brain degeneration (see “On the web”).
This establishes a powerful link between protein structure
and protein function.
Exploring protein structure on Foldit
As a further exploration of protein structure, students are introduced to the online protein folding game Foldit, in which
players collaborate to find the optimal folded structure of a
protein based on its sequence. In 2011, Foldit players solved
the structure of a retroviral protease (Khatib and DiMaio
2011). The students begin by watching an interview with the
creator, Adrien Treuille (see “On the web”), who talks about
how citizen science can help solve scientific problems.
The Foldit site provides instructions for educators using
the program with their classes (see “On the web”). First you
Modeling Molecular Machinery
Grading rubric
Maximum
Points
Background Information
9
The function of the protein is explained (3 pts.).
The site of protein activity is described (3 pts.).
The relevance of the protein (importance, interest) is discussed (3 pts.).
Structural Information
5
The overall secondary structure of the protein is described (2 pts.).
Two specific examples of forces that are important for the tertiary structure are given (2 pts.).
The quaternary structure (along with any additional subunits) is described (1 pt.).
Interactions
6
Two natural or synthetic molecules that interact with the protein are given (2 pts.).
The site of interaction (and any relevant forces or conformation changes) are described (4 pts.).
Protein Function
5
The relationship of protein structure to protein function is described (2 pts.).
The structural and functional impact of one mutation is described (2 pts.).
One potential application for medicine or industry is given (1 pt.).
Pictures
8
Poster includes four student-generated pictures of protein structure that illustrate features
described in the previous sections (2 pts. each).
References
Sources are cited in APA format (2 pts. each).
2
Total
35
create a team (our mascot is the kangaroo, so we became the
pRooTeens). Students then create individual accounts and
join the team, at which point you can follow their progress. I
found it helpful to have a common format for students to use
when setting up their individual user names (school name–
first name–last initial). (Note: Follow your school district’s
rules regarding protecting students’ online privacy, which
may include getting a signed permission slip from parents.)
In our Genetic Engineering course, students are asked
to complete all of the introductory tutorial puzzles in Foldit
(Figure 3, p. 54). These puzzles begin by introducing important aspects of protein folding, including packing, ionic and
disulfide bonds, hydrogen bonding, ß-sheets, and α-helices.
As students advance, they must find the set of strategies that
creates the most favorable folded structure. Just as a designer
February 2015
53
must consider structure, cost, aesthetics, and function, the
students have to begin making trade-offs to address multiple
forces that may conflict. They may find that adding hydrogen bonds to stabilize one part of a protein causes destabilizing collisions in another region or creates a protein that is too
rigid to undergo conformational change. In the final puzzles
students can make targeted changes to the protein sequence
and observe the effect on the folded structure. Although
working at a molecular level, students are using the same
process of design thinking that an engineer would apply to
the development of a new product. Incorporating engineering design throughout the sciences is a central message of the
Next Generation Science Standards.
Foldit engages students like a video game: The score increases or decreases with each move, and targeted hints provide differentiated feedback so each student can complete the
challenges. Students report that they enjoy interacting with
real people in the Foldit community when they need help
with a challenge.
F IGUR E 3
Students working on the
introductory protein folding
puzzles on Foldit.
Computer modeling of protein structure
In the capstone project for the unit on protein structure,
each student is asked to analyze the structure and function
of a protein and present a poster at Science Night (Figure 2,
p. 52). Students browse the featured proteins on the online
resources Proteopedia and the Protein Data Bank (PDB) of
the Research Collaboratory for Structural Bioinformatics
(RSCB) (see “On the web”) to select a protein to study. Protopedia groups proteins by topic, so students can easily find
a protein related to a specific interest (diseases, toxins, drugtargets, etc.). Many are surprised to find they are already familiar with such proteins as insulin, serotonin transporter,
keratin, collagen, lactase, gluten, and human growth hormone. Students examine the folded structure of the protein
and focus on regions important for function, such as binding
54
The Science Teacher
sites, membrane spanning domains, or enzyme active sites.
They also consider structural variations and mutations that
affect protein function, and they research molecules (natural or synthetic) that can bind to their protein of interest.
Looking at interacting molecules can also lead to an interesting discussion of rational drug design and how knowing
the structure of a protein can aid in identifying or designing
target drugs. We followed this up in class using the HHMI
resources on the targeted design of Gleevec as an inhibitor
of the cancer-causing Bcr-Abl mutation (see “On the web”).
Students begin learning how to use protein visualization
software with a tutorial provided on the RSCB Protein Data
Bank (see “On the web”). Most students choose to use the
Protein Workbench program, because it offers many options
for displaying the protein structure. After helping each other
through the Foldit challenge, students readily help their peers
as they learn new tricks and shortcuts in the visualization
software. The students move quickly from indiscriminately
zooming and spinning their proteins to achieving specific
goals. For example, one student created images highlighting
Modeling Molecular Machinery
FI G U R E 4
Images from the student structure-function posters.
Figure 4A is from a student analysis of the Alzheimer’s protein ApoE. It shows the amino acids that are altered in
the three most common variants. Figure 4B is from a student poster on COX-2, which is the target of NSAID pain
medications such as aspirin and ibuprofen.
A
B
the amino acids that differ in the variants of the Alzheimer’s
protein ApoE (Figure 4A). Another student presented images that explained how NSAIDS (such as ibuprofen) reduce
pain signals by inhibiting the enzyme COX-2 (Figure 4B).
For the project, each picture must support a section of the
written analysis. It’s not enough for images to look good; they
must communicate specific information. Accordingly, students think carefully about how to adjust the options (scale,
angle, bonds, backbone) to achieve the view that best supports their points. Using computer modeling software allows
students to execute their vision in a professional way even if
they are not skilled at drawing.
Conclusion
By the end of the course students can discuss cellular proteins as concrete objects with inherent shapes and related
functions. They can see how inter- and intramolecular forces
gave rise to these structures and how mutations affect protein shape. Much of the students’ comfort with these ideas
comes from playing the online game Foldit, which has stu-
dents advising each other to “wiggle the side chains so they
pack together” and “add some hydrogen bonds to that helix.”
Students applied their understanding to the analysis of a real
protein, using computer models to visualize tertiary structures such as hydrophobic pockets and helix bundles.
Students responded positively to both the Foldit assignment and the protein structure-function project. Some expressed frustration that the initial assignments on Molecular
Workbench repeated material they had learned previously.
In the future I would pre-assess and then include more advanced Molecular Workbench models, such as Designer Proteins, for students who have already mastered transcription
and translation. Conversely, first-year biology students might
need to progress more slowly through the introductory lessons. Some students also had difficulty managing their time
for the structure-function project and asked to have deadlines for individual components of the project.
In the second half of the Genetic Engineering course, students consider the ethics of gene therapy, genetic engineering, and synthetic biology. It was interesting to see how the
February 2015
55
FI G U R E 5
Proteins selected for student projects.
Students selected proteins that represented a range of interests from familiar diseases to cosmetics to deadly
poisons. The list below shows the proteins selected by one class, along with a brief description of the protein’s
function.
Retinoblastoma protein
(Rb)
A tumor suppressor gene that is mutated in many types of cancer. Students who have
received Gardasil might be interested to know that the Rb protein is a target in some
HPV-induced cancers.
Sonic hedgehog (Shh)
Involved in fetal development and also a potential target for drugs to treat basal-cell
carcinoma (a common skin cancer).
Estrogen receptor (ER)
An intracellular receptor that responds to estrogen signaling. The ER activity of breast
cancer tumors is important in determining the course of treatment.
Phosphatase and tensin
homolog (PTEN)
A phosphatase involved in cell signaling. PTEN is a common mutation in prostate
cancer. PTEN mutations have also been linked to autism-spectrum disorders.
Parkin
Part of the protein-degradation pathway. Mutations in Parkin cause a heritable form of
Parkinson’s disease.
Apolipoprotein E (ApoE) Involved in lipid transport. The ApoE4 variant is a risk-factor for Alzheimer’s disease.
Amyloid Precursor
Protein (APP-b)
The major component of the protein tangles (plaques) that are found in the brains of
Alzheimer’s patients.
Serotonin transporter
(SERT or 5-HTT)
Responsible for the recycling of the serotonin neurotransmitter. SERT is the target of
selective serotonin reuptake inhibitors (SSRIs) such as Prozac.
Leptin
A hormone that regulates the amount of fat stored by the body.
Cyclooxygenase (Cox)
Enzymes that are the target of NSAID painkillers such as ibuprofen and Celebrex.
Insulin
Pancreatic hormone that controls the levels of glucose in the blood. The loss of insulin
results in diabetes.
Keratin
A fibrous protein found in hair, nails, and skin. Keratin is a frequent ingredient in
shampoos and lotions and it is used in some hair-straightening processes.
Ricin
Ricin is a deadly toxin that can be isolated from castor beans. Chemistry teacher Walter
White made use of ricin on the TV show Breaking Bad.
students’ new understanding of cellular machinery affected
their discussion of bioethical issues. These issues seemed less
abstract to our students because they could connect them to
their previous work. Following these learning activities, our
students could extend their previous thinking about “gene
therapy” or “genetic engineering” and instead consider “replacing a protein” or “changing a protein.” This allowed
them to step away from the polarizing views often presented
by the media, and it led to richer discussions and more informed arguments. ■
Christine Hunter ([email protected]) is chair of the
Science Department at the Abington Friends School in Jenkintown, Pennsylvania.
56
The Science Teacher
Acknowledgments
The author wishes to thank Andrew Bickford and the anonymous
reviewers for their critical reading of this manuscript.
On the web
Genetic engineering course website: https://sites.google.com/a/
abingtonfriends.net/genetic-engineering/
Protein Synthesis and Folding
Molecular Workbench: http://mw.concord.org/
NIGMS resources on structural biology and protein folding:
http://1.usa.gov/1FHtPY3
Protein-folding exercise from Clayton State University: http://
bit.ly/1y3Enwv
Modeling Molecular Machinery
Once students have a firm foundation in
DNA transcription and translation and
understand protein synthesis, we discuss
the levels of protein structure and the
intermolecular and intramolecular forces
that promote folding.
FI G U R E 6
Timeline of activities.
The activities described in this article (along with
lectures and discussions) comprised an eightweek unit. Students progressed at their own pace;
approximate number of 45-minute class periods
required is shown below. The class website contains
additional readings and activities for students who
complete the required work early.
1.
Molecular Workbench: Set up accounts and
DNA to Protein (3)
2. Molecular Workbench: Intermolecular
Interactions (2)
3. Molecular Workbench: Protein Folding (2)
4. Protein Models (1)
5. Prion Documentary and Readings (2)
6. Video introduction to FoldIt creation of FoldIt
accounts (1)
7. Protein Data Base Tutorial (2)
8. Introduction to Protein Structure-Function
Project and selection of proteins (1)
9. Class time to complete the FoldIt project and
Sructure-Function Project (12)
Prions and amyloid-forming proteins
Exploration of fibril-forming proteins from the Institute for
Complex Adaptive Matter: http://bit.ly/11IIsxi
NBC News clip on 2012 case of BSE in California: http://
nbcnews.to/12DZj4y
Prions and kuru, University of Utah: http://bit.ly/1A7hPOl
Science Friday radio program on fatal familial insomnia:
http://n.pr/1yuldCF
Science in School article on prions and BSE: http://bit.ly/1vZprV2
Computer modeling of protein structure
Foldit instructions for educators: http://bit.ly/15Mq8pa
HHMI resources on Gleevec and Bcr-Abl: http://bit.ly/1v3MuqP
NOVA Science Now profile on Foldit creator Adrien Treuille:
http://to.pbs.org/1y3GMr8
Proteopedia: protein structures: http://bit.ly/1B5lOOI
RSCB protein data bank: http://bit.ly/1vARisF
RSCB protein data bank tutorial: http://bit.ly/1yazB5o
References
Costandi, M. 2013, Feb. 14. Proteins behind mad-cow disease also
help brain to develop. Nature. http://bit.ly/1vIIYG3
Khatib, F., and F. DiMaio. 2011, Sept. 18. Crystal structure of a
monomeric retroviral protease solved by protein folding game
players. Nature Structural and Molecular Biology 18: 1175–1177.
http://bit.ly/1ndsRzf
NGSS Lead States. 2013. Next Generation Science Standards: For
states, by states. Washington, DC: National Academies Press.
Tempsick, R. 2011. Building protein structures and the molecule of
the month. RCSB PDB Newsletter 49 (Spring 2011): 6–7.
White, B. 2006. A simple and effective protein folding activity
suitable for large lectures. CBE–Life Sciences Education 5 (3):
264–269. http://1.usa.gov/1rNeu1Y.
February 2015
57