TITLE OF LESSON/MODULE
Using “Foldit,” a Protein Modeling Video Game, to Inspire Interest in Protein Structure and Function
AUTHOR(S) AND SCHOOL AFFILIATION(S)
Luke Sandro, Springboro High School
OVERVIEW
This module was inspired by the research in a biochemistry lab at Wright-Patterson Air Force Base in Dayton,
OH. One of the widely used tools in this lab was protein modeling software, used to find the most likely conformations
of particular proteins, both naturally occurring and synthetic. While the software they use is expensive and difficult to
learn, there is a similar, free program, “Foldit,” (available at http://fold.it/portal/info/science) which allows anyone to
participate in protein modeling. This is an incredibly engaging program for several reasons. First, it presents protein
modeling as an online “game,” in which players earn more points for more energetically favorable protein
conformations, and are competing against players nationwide. Second, not only does this program provide players the
tools to discover the principles of protein modeling, but once players reach a certain level, their work is transmitted to a
national database where it may actually be used by scientists to discover previously unknown protein structures.
In this 3-day lesson, students will use Foldit as a gateway to discovering aspects of genetics and protein structure
and function. During day one, student groups use various resources to discover the answers to questions that prepare
them to understand the game. During day two, students play the game’s tutorial, answering questions along the way
that guide them to real-world understanding of protein structure. Day 3 is an all-out competition, where groups that
score highest on individual proteins, as well as those that finish the most proteins overall, are the winners.
TYPE/LEVEL OF INQUIRY 1= Open Inquiry
3= Guided Inquiry
Day 1=inquiry level 3, Days 2-3= inquiry level 1-2
GRADE LEVEL/COURSE
Grade 9-10/CP Biology, Biology
ANTICIPATED LENGTH OF LESSON/MODULE (MINUTES)
2-3 Class periods
PREREQUISITE KNOWLEDGE
Students can approach days 2 and 3 of this module from any experience level, but to get the most out of it, a good
knowledge of the process of gene expression and the structure and function of proteins is good.
STATE/NATIONAL STANDARDS
Course: Biology
Course Content:
Heredity

Structure and function of DNA in cells

Cell structure and function
Cells
Content Elaboration:

“Genes are segments of DNA molecules. The sequence of DNA bases in a chromosome determines the sequence
of amino acids in a protein. Inserting, deleting or substituting segments of DNA molecules can alter genes.”
“The sequence of DNA bases on a chromosome determines the sequence of amino acids in a protein. Proteins
catalyze most chemical reactions in cells. Protein molecules are long, usually folded chains made from
combinations of the 20 typical amino-acid sub-units found in the cell. The function of each protein molecule
depends on its specific sequence of amino acids and the shape the chain takes as a result of that sequence.”
MATERIALS
Computer with “Foldit” program installed, internet connection (useful but not required until past tutorial),
student worksheets.
INSTRUCTIONAL PLAN (INCLUDE STUDENT SHEETS SEPARATE FROM THIS DOCUMENT.)
A. INTRODUCTION
The teacher should briefly review material on gene expression and protein synthesis, and then abruptly ask a question
like “who likes video games?” Students can discuss and describe their favorite video games, and why they like them.
One popular aspect of many of these games is the ability to compete against other players across the world. The
teacher should seize on this aspect, explaining that, provided the students’ understand proteins well enough, this is
exactly what they’ll be doing. The teacher should stress that protein modeling is a very exciting frontier of science, and
is going on in thousands of labs in the world. Students will be further engaged with the idea that Foldit is an online
game that allows them not only to compare their high scores to others in the world, but also, if they get good enough, to
participate in this research, with their solved molecules sent to a national database.
B. ACTIVITY
Day 1: Review-- After the above introduction, students form groups (adjust these to the number of
available computers—anything from 2-4 students to a group is appropriate) and use their textbook, the
internet, and Student Page 4 (Foldit’s main info web page) to complete Student Page 1. Teacher should
be circulating, helping, and emphasizing that this knowledge will be essential for day 2 when they play
the video game.
Day 2: Learning from Foldit--Student groups work their way through the tutorial (called “Intro Puzzles”
in the Foldit menu), completing the folding tasks while answering questions on Student Page 2 which
connect their prior knowledge, their answers to day 1’s activity, to the tutorial. Teacher should be
circulating, helping students learn the tools of the game (in particular, the teacher should play the
game to get familiar with the “shake,” “wiggle,” and “rubber band” tools before running this module.)
Day 3: The Contest—Student groups should be turned loose to compete against other groups, with the
teacher confirming individual scores of completed molecules on Student Page 3. The competition can
be organized in any number of ways, but one possible scenario would be to have a minimum number of
completed molecules for a passing grade, and then prizes or extra credit for the group with a) the most
completed molecules, and b) the highest scores on particular molecules.
C. POST ACTIVITY DISCUSSION
Discussion when day 3 is completed should focus on how in-demand this particular discipline’s
knowledge is, and how understanding of protein structure and other biochemical principles is becoming
essential to most biological areas. Since Foldit is a free program, the teacher should also encourage students to
compete at home, and see how many molecules they can solve—students with exceptional skills at this game
can become deeply engaged and encouraged to find opportunities in university biochemistry programs.
EXTENSIONS
Since Foldit is a free program, students can download it at home. If enough students become skilled at the
game, the possibilities for extensions are huge, since at a certain point they are working on proteins with actual
unknown conformations. The links to research biochemistry are quite strong, and so especially skilled students might be
prompted to inquire at local universities about research opportunities.
ASSESSMENT
The teacher will be observing and prompting students throughout the lesson. For day 1, answers on student
pages will be graded after activity. For Day 2, teacher should be constantly prompting and observing students as they
work, then will grade questions on student page. For day 3, teacher signs off on each completed molecule, and can
decide whether to require completion of all molecules or a minimum number.
REFERENCES
1. http://fold.it/portal/info/science
2. Miller, K. R., & J. S. Levine (2002) Biology (A high school biology text). Prentice Hall Co., 1041 p.
3. http://www.dur.ac.uk/stat.web/Bioinformatics/aminoacids.htm
STUDENT PAGE 1—REVIEW OF GENE EXPRESSION AND PROTEIN STRUCTURE AND FUNCTION
TEACHERS—ANSWERS ARE IN RED—SIMPLY DELETE THEM TO CREATE READY-TO-USE STUDENT PAGES
WORKING IN GROUPS, USE RESOURCES AVAILABLE (TEXTBOOK, INTERNET, “FOLDIT” INFO PAGE) TO ANSWER
THE FOLLOWING REVIEW QUESTIONS BEFORE YOU PLAY “FOLDIT.”
1. What does DNA actually do in your cells? It codes for amino acids which form proteins
2. Explain, in short essay format with diagrams, how DNA and RNA work together to express a gene—
diagrams may be copied from resources, but you must list those sources and your essay text must be in
your own words. Terms to include: complementary bases, DNA, mRNA, editing, ribosomal subunits,
tRNA, amino acid, peptide bond, polypeptide, protein
Using complementary base pairing, DNA is transcribed into mRNA in the nucleus. After being edited,
mRNA exits the nucleus and attaches to the large and small ribosomal subunits. Each 3 bases of mRNA
attract one molecule of tRNA, which has 3 complementary bases and carries a particular amino acid.
As the mRNA moves through the ribosome, new tRNA molecules bring new amino acids, which get
attached to each other using peptide bonds. This forms a growing polypeptide chain, which eventually
becomes a protein.
3. How many DNA bases code for one amino acid? 3
4. How many amino acids are there in living things? 20
5. Explain, using diagrams, the difference between primary, secondary, and tertiary structure in proteins
Primary structure refers to the order of amino acids. Secondary refers to specific folds like alpha helices
and beta sheets. Tertiary structure is the overall folding of the protein.
6. Explain what a hydrogen bond is
Hydrogen bonds are attractions between hydrogens and electronegative atoms like Oxygen, Nitrogen
or Fluorine.
7. What secondary structure type in proteins is caused by hydrogen bonding?
Beta sheets
8. What is it about a protein’s shape that is so important?
Shape is what determines the function of the protein.
9. Find 5 different types of jobs that proteins do in our bodies.
Almost infinite range of answers here.
10. Amino acids determine the shape of proteins because of the chemical properties of what Foldit calls
“side chains,” which we sometimes call “R groups.” Find and copy a diagram of the amino acid glycine,
circling the side chain or R group.
(Use any text or internet resource to find diagram—the side group is the hydrogen atom)
Each of the amino acids has a different side chain. Please answer the questions about the amino acids that
have the following properties:
11. Some amino acids have side chains that are electrically charged. That charge can be positive
or negative. Find the amino acids that have:
a. Positive side chains Arginine, Histidine, Lysine
b. Negative side chains Aspartic acid, Glutamic Acid
c. What would happen if two positively charged side chains got close to each other because of the
way a protein was folded? They would repel each other
d. What would happen if a negative and a positive one got close to each other? They would
attract each other
12. Some amino acids have side chains are polar, but not enough to have a charge. Name those.
Serine, Threonine, Asparagine, Glutamine
13. Many amino acids have nonpolar side chains. Name them.
Alanine, Isoleucine, Leucine, Methionine, Phenylalanine, Tryptophan, Tyrosine, Valine
14. What property, related to water, does any nonpolar molecule have (remember phospholipids in the
cell membrane to help answer this)? They are hydrophobic
15. In a folded protein in your body, which is mostly water, where would you expect to find most of the
nonpolar side chains? On the interior of the molecule, away from the water they’re floating in
16. The remaining three amino acids are different enough that they don’t fit well in any of the above
categories. Name them. Cysteine, Glycine, Proline
17. Which of these amino acids has a side chain that can form a special bond called a disulfide bond?
Cysteine
STUDENT PAGE 2—LEARNING FROM FOLDIT
IN YOUR GROUPS, OPEN THE PROGRAM “FOLDIT” AND CHOOSE “INTRO PUZZLES.” NOTE THAT THERE ARE
EIGHT SUBCATEGORIES OF PUZZLES. YOU NEED TO ATTEMPT AT LEAST ONE OF THE FIRST FOUR
SUBCATEGORIES, AND ANSWER THE QUESTIONS THAT GO WITH IT. USE YOUR ANSWERS TO YESTERDAY’S
QUESTIONS TO HELP YOU ANSWER TODAY’S. TRY TO SOLVE AS MANY MOLECULES AS YOU CAN.
A. SIDECHAINS
1. What color are the sidechains?
Blue and orange
2. What are two possible reasons a “clash” might exist?
Positive side chains too close, negative side chains too close, polar and nonpolar too close
B. BACKBONE PACKING—make sure you’re watching the score at the top!
1. What are the actual functional groups that make up the “backbone” of a protein?
Carboxyl group, amino group
2. What is the name of the bond between amino acids in the backbone? Peptide bond
3. In “close the gap,” there is an example of secondary structure. What is it? The two coils (alphahelices)
C. HYDROGEN BONDING—don’t forget to “stop” wiggling when you have your highest score!
1. What kind of secondary structure are you forming by creating hydrogen bonds with your wiggle
tool? Beta sheets
D. HYDROPHOBICS AND HYDROPHILICS
1. Which actual amino acids are hydrophobic?
Alanine, Isoleucine, Leucine, Methionine, Phenylalanine, Tryptophan, Tyrosine, Valine
2. Why do they want to be buried on the interior of the protein? They repel water
3. What color are the hydrophobic amino acids in the game? Orange
4. What color are the hydrophobic ones? Blue
STUDENT PAGE 3—THE CONTEST
NOW THAT YOU KNOW HOW TO USE FOLDIT, IT IS TIME TO COMPETE! BEGINNING WITH THE “TOOLS AND
TYPES” SUBCATEGORY, YOUR MISSION IS TO A) COMPLETE MORE MOLECULES THAN THE OTHER GROUPS,
AND B) GET THE HIGHEST SCORE ON EACH INDIVIDUAL MOLECULE. WHEN YOU FINISH EACH MOLECULE,
WRITE DOWN YOUR SCORE AND HAVE A TEACHER OR AIDE SIGN OFF IN THE BLANK NEXT TO IT.
E. TOOLS AND TYPES
5-1 __________ 5-2 _____________ 5-3 _____________ 5-4 ___________ 5-5 ______________
F. SEQUENCES
6-1 __________ 6-2 ______________ 6-3 ______________
G. PROTEIN DESIGN
7-1 __________ 7-2 ______________ 7-3 ______________ 7-4 __________________
H. MORE MOLECULES
8-1 __________ 8-2 ______________ 8-3 ______________ 8-4 __________________
IF YOU FINISH THE TUTORIAL, MOVE ON TO THE “SCIENCE PUZZLES.” THESE ARE
REAL MOLECULES THAT YOU CAN WORK ON!
STUDENT PAGE 4—THE SCIENCE BEHIND FOLDIT (REFERENCE PAGE, TO BE USED FOR DAY 1 AND 2)
The Science Behind Foldit
Foldit is a revolutionary new computer game enabling you to contribute to important scientific research. This page describes
the science behind Foldit and how your playing can help.
What is protein folding?
Folded up Puzzle 48 (+) Enlarge This Image
What is a protein? Proteins are the workhorses in every cell of every living thing. Your body is made up of trillions of cells, of all
different kinds: muscle cells, brain cells, blood cells, and more. Inside those cells, proteins are allowing your body to do what it does:
break down food to power your muscles, send signals through your brain that control the body, and transport nutrients through your
blood. Proteins come in thousands of different varieties, but they all have a lot in common. For instance, they're made of the same stuff:
every protein consists of a long chain of joined-together amino acids.
What are amino acids? Amino acids are small molecules made up of atoms of carbon, oxygen, nitrogen, sulfur, and hydrogen. To
make a protein, the amino acids are joined in an unbranched chain, like a line of people holding hands. Just as the line of people has
their legs and feet "hanging" off the chain, each amino acid has a small group of atoms (called a sidechain) sticking off the main chain
(backbone) that connects them all together. There are 20 different kinds of amino acids, which differ from one another based on what
atoms are in their sidechains. These 20 amino acids fall into different groups based on their chemical properties: acidic or alkaline,
hydrophilic (water-loving) or hydrophobic (greasy).
Unfolded (and unstable) Puzzle 48(+) Enlarge This Image
What shape will a protein fold into? Even though proteins are just a long chain of amino acids, they don't like to stay stretched out in
a straight line. The protein folds up to make a compact blob, but as it does, it keeps some amino acids near the center of the blob, and
others outside; and it keeps some pairs of amino acids close together and others far apart. Every kind of protein folds up into a very
specific shape -- the same shape every time. Most proteins do this all by themselves, although some need extra help to fold into the
right shape. The unique shape of a particular protein is the most stable state it can adopt. Picture a ball at the top of a hill -- the ball will
always roll down to the bottom. If you try to put the ball back on top it will still roll down to the bottom of the hill because that is where it
is most stable.
Why is shape important? This structure specifies the function of the protein. For example, a protein that breaks down glucose so the
cell can use the energy stored in the sugar will have a shape that recognizes the glucose and binds to it (like a lock and key) and
chemically reactive amino acids that will react with the glucose and break it down to release the energy.
What do proteins do? Proteins are involved in almost all of the processes going on inside your body: they break down food to power
your muscles, send signals through your brain that control the body, and transport nutrients through your blood. Many proteins act as
enzymes, meaning they catalyze (speed up) chemical reactions that wouldn't take place otherwise. But other proteins power muscle
contractions, or act as chemical messages inside the body, or hundreds of other things. Here's a small sample of what proteins do:









Amylase starts the process of breaking down starch from food into forms the body can use.
Alcohol dehydrogenase transforms alcohol from beer/wine/liquor into a non-toxic form that the body uses for food.
Hemoglobin carries oxygen in our blood.
Fibrin forms a scab to protect cuts as they heal.
Collagen gives structure and support to our skin, tendons, and even bones.
Actin is one of the major proteins in our muscles.
Growth hormone helps regulate the growth of children into adults.
Potassium channels help send signals through the brain and other nerve cells.
Insulin regulates the amount of sugar in the blood and is used to treat diabetes.
Proteins are present in all living things, even plants, bacteria, and viruses. Some organisms have proteins that give them their special
characteristics:



Photosystem I is a collection of proteins in plants that captures sunlight for photosynthesis.
Luciferase catalyzes the chemical reaction that makes fireflies glow.
Hemagglutinin helps the influenza virus invade our cells.
You can find more information on the rules of protein folding in our FAQ.
Why is this game important?
What big problems is this game tackling?


Protein structure prediction: As described above, knowing the structure of a protein is key to understanding how it works
and to targeting it with drugs. A small protein can consist of 100 amino acids, while some human proteins can be huge (1000
amino acids). The number of different ways even a small protein can fold is astronomical because there are so many degrees
of freedom. Figuring out which of the many, many possible structures is the best one is regarded as one of the hardest
problems in biology today and current methods take a lot of money and time, even for computers. Foldit attempts to predict the
structure of a protein by taking advantage of humans' puzzle-solving intuitions and having people play competitively to fold the
best proteins.
Protein design: Since proteins are part of so many diseases, they can also be part of the cure. Players can design brand new
proteins that could help prevent or treat important diseases.
A human protein (+) Enlarge This Image
How does my game playing contribute to curing diseases?
With all the things proteins do to keep our bodies functioning and healthy, they can be involved in disease in many different ways. The
more we know about how certain proteins fold, the better new proteins we can design to combat the disease-related proteins and cure
the diseases. Below, we list three diseases that represent different ways that proteins can be involved in disease.



HIV / AIDS: The HIV virus is made up largely of proteins, and once inside a cell it creates other proteins to help itself
reproduce. HIV-1 protease and reverse transcriptase are two proteins made by the HIV virus that help it infect the body and
replicate itself. HIV-1 protease cuts the "polyprotein" made by the replicating virus into the functional pieces it needs. Reverse
transcriptase converts HIV's genes from RNA into a form its host understands, DNA. Both proteins are critical for the virus to
replicate inside the body, and both are targeted by anti-HIV drugs. This is an example of a disease producing proteins that do
not occur naturally in the body to help it attack our cells.
Cancer: Cancer is very different from HIV in that it's usually our own proteins to blame, instead of proteins from an outside
invader. Cancer arises from the uncontrolled growth of cells in some part of our bodies, such as the lung, breast, or skin.
Ordinarily, there are systems of proteins that limit cell growth, but they may be damaged by things like UV rays from the sun or
chemicals from cigarette smoke. But other proteins, like p53 tumor suppressor, normally recognize the damage and stop the
cell from becoming cancerous -- unless they too are damaged. In fact, damage to the gene for p53 occurs in about half of
human cancers (together with damage to various other genes).
Alzheimer's: In some ways, Alzheimer's is the disease most directly caused by proteins. A protein called amyloid-beta
precursor protein is a normal part of healthy, functioning nerve cells in the brain. But to do its job, it gets cut into two pieces,
leaving behind a little scrap from the middle -- amyloid-beta peptide. Many copies of this peptide (short protein segment) can
come together to form clumps of protein in the brain. Although many things about Alzheimer's are still not understood, it is
thought that these clumps of protein are a major part of the disease.
This is an example of a puzzle that a human can see the obvious answer to - fix the
sheet that is sticking out! (+) Enlarge This Image
What other good stuff am I contributing to by playing?
Proteins are found in all living things, including plants. Certain types of plants are grown and converted to biofuel, but the conversion
process is not as fast and efficient as it could be. A critical step in turning plants into fuel is breaking down the plant material, which is
currently done by microbial enzymes (proteins) called "cellulases". Perhaps we can find new proteins to do it better.
Can humans really help computers fold proteins?
We’re collecting data to find out if humans' pattern-recognition and puzzle-solving abilities make them more efficient than existing
computer programs at pattern-folding tasks. If this turns out to be true, we can then teach human strategies to computers and fold
proteins faster than ever!
You can find more information about the goals of the project in our FAQ.