To Fold Or Not To Fold?

An exploration of
the exciting world
of protein folding for
high school chemistry
or biology teachers
and students.
Claudia Winkler and Gary Benz

Animation of the folding of

villin, a well known protein
Activity 1 - Vocabulary
Sharpen your skills!
• What do the following words mean:
amino-acids, bonds, carbon, folding,
hydrogen, nitrogen, oxygen, protein,
polymer, residue, sulfur, synthesize,
villin?

• We will briefly explore their meaning in

the next few pages, so that the
concepts we are introducing in the
slides ahead might be clearer.
 Vocabulary: Amino-Acid
• Amino-acids are the building
blocks of proteins.
• They are characterized by the
presence of a carboxyl group
(COOH) and an amino group
(NH3) attached to the same
carbon (called alpha carbon).
• The letter R represents
succinctly the “rest” to which
the amino-acid group is
attached.
 Vocabulary: Chemical Bonds
• Except for noble gases which have achieved the state of
“nirvana” for their atoms, i.e. they have a complete outer
shell of electrons, all other elements in nature pair up with
other elements to complete their outer shell. This process is
called “chemical bonding”.

• Bonds most relevant to organic chemistry are: covalent

bonds and hydrogen bonds.

– Covalent bonds are characterized by sharing of electrons

between the atoms “bonding with each other” to form a
molecule.

– Hydrogen bonds keep together polar molecules, i.e. molecules

which have uneven distribution of electric charge.

– Hydrogen bonds can also occur between part of the same

polymer when there is charge polarity between different parts
of the polymer.
 Vocabulary: Carbon
• (Latin: carbo, charcoal)
Carbon, an element of Atomic number 6
prehistoric discovery, is very
widely distributed in nature.
It is found in abundance in Atomic Symbol C
the sun, stars, comets, and
atmospheres of most planets.
Atomic mass 12.011 u
• Carbon is the source of
energy for life through Electron [He]2s22p2
carbohydrates, just like a Configuration
burning log is a source of
energy to a cold room.
 Vocabulary: Hydrogen
• (Greek: hydro, water, Atomic 1
and genes, forming) number
Hydrogen is the most
abundant of all elements Atomic H
in the universe. symbol
Atomic mass 1.0070 u
• The heavier elements Electron 1s1
were originally made Configuration
from Hydrogen or from
other elements that
were originally made
from Hydrogen.

• Used in rocket fuel.

 Vocabulary: Oxygen
• Greek: oxys, sharp, acid,
and genes, forming; acid
former) Oxygen is the Atomic 8
number
third most abundant
element found in the sun. Atomic O
symbol
Oxygen is vital to the
Atomic mass 15.9994 u
respiration of living
organisms. Electron [He]2s22p4
Configuration
• Oxygen is responsible for
the bright red and yellow-
green colors of the Aurora.
• Essential element for
combustion (i.e. burning).
 Vocabulary: Nitrogen
• (Latin Nitrum, Greek.
Nitron, native soda; genes, Atomic 7
forming) number
• Nitrogen gas (N2) makes Atomic N
up 78.1% of the Earth’s symbol
air, by volume. Atomic mass 14.00674
• Nitrogen is found in all
living systems as part of Electron [He]2s22p3
the makeup of biological Configuration
compounds.
• Ammonia (NH3) is the
most important
commercial compound of
nitrogen, with a very
pungent smell, used in
cleaning supplies.
 Vocabulary: Sulfur
• (Sanskrit, sulvere; Latin
sulpur) Known to the Atomic 16
ancients; referred to in number
Genesis as brimstone. Atomic S
• Sulfur occurs native in the symbol
vicinity of volcanoes and hot Atomic mass 32.6
springs.
Electron [Ne]3s23p4
• It is widely distributed in Configuration
nature in various minerals
(iron pyrites, galena,
sphalerite, cinnabar, stibnite,
gypsum, epsom salts,
celestite, barite, etc.)
• Sulfur is found in meteorites.

Yellowstone hot springs

 Vocabulary: Proteins
• Proteins are necklaces of amino acids, i.e. long chain
molecules. Proteins are the basis of how biology gets
things done.

• As enzymes, they are the driving force behind all of

the biochemical reactions which makes biology work.

• As structural elements, they are the main constituent

of our bones, muscles, hair, skin and blood vessels.

• As antibodies, they recognize invading elements and

allow the immune system to get rid of the unwanted
invaders.
Vocabulary: (Protein) Folding
• Proteins are formed by unique sequences of
amino-acids. However, only knowing the
sequence tells us little about what the protein
does and how it does it.

• In order to carry out their function (for

instance as enzymes or antibodies), proteins
must take on a particular shape, also known
as a "fold." Thus, proteins are truly amazing
machines: before they do their work, they
assemble themselves! This self-assembly is
called "folding."
 Vocabulary: Polymer
• Polymers are chemical compound
with high molecular weight consisting
of a number of structural units (called
monomers) linked together by
covalent bonds.

• A structural unit is a group having Rubber tree

two or more bonding sites.

• Many polymers occur in nature, such

as silk, cellulose, caoutchouc (latex),
which is natural rubber coming from
the rubber tree, and proteins. Many
others are man made (such as
plastic), foam.
 Vocabulary: Residue
• When amino acids connect with each
other to form a a specific protein, they
do so through a special kind of covalent
bond that is called “peptide bonds”.

• In the formation of the bond, water is

released. What remains is called a
“residue”. Residues are the beads of the
necklace we introduced before.
 Vocabulary: Synthesize
• To synthesize means to bring together. In
chemistry it means to make a product from other
products.

• For instance A+B -> C means that element A is

added to element B to synthesize element C.

• Since the incredible development of Organic

Chemistry in the 1900s, thousands of new
compounds have been synthesized, in the fields
of textiles, building materials, plastic, paints,
cosmetics, etc.
 Vocabulary: Villin
• Villin is a protein that
gives structure to
intestinal villi (shown in
the model to the right).

• Intestinal villi augment

the surface of the
intestine to increase
food absorption.

• However intestinal villi

need to be “stabilized”,
to add rigidity.
 Why Villin?
• We chose villin as a model for
protein folding.

• Villin is a well known protein

whose folding processes have been
studied and are understood among
the scientific community.
 Villin is a protein
• It is made up of 36 amino acid “residues”.
• It has been heavily studied experimentally
and by simulation since it is perhaps one
of the smallest, fastest folding proteins.
What makes proteins
different from each other?
• Proteins are synthesized as linear
polymers (i.e. chains) of amino
acids.

• Once formed, the protein chain,

does not remain straight for long.
 Form determines function
• Suppose you have some molten iron. You
may turn it into nails, hammers, wrenches,
etc. What makes these tools different from
each other is their form (i.e. their shape and
structure)

• Similarly proteins, though basically being

built as similar chains of amino acids, very
rapidly fold onto their own “correct” form, so
as to be able to carry out the function that is
assigned to them
 Folding is critical
• When proteins do not fold correctly (i.e. they "mis-
fold") there can be serious effects, including many
well known diseases, such as Alzheimer's, mad cow
disease (also known as Creutzfeldt-Jakob disease,
prions, bovine spongiform encephalopathy, scrapie)
and Parkinson's disease.

• Understanding protein folding is critical in the

medical and clinical professions and as such it is
the subject of extensive research.
 Villin folds
• Immediately after the villin
polymer is synthesized, it starts to
fold over itself to form a perfectly
defined geometrical structure.

• There is only one “correct” shape

that villin can fold into to perform
its biological actions.
 Villin model
• To represent folding in villin, we
have built a model.

• The purpose of this model, to be

displayed on the floor of the
Exploratorium, is to simulate the
correct folding of villin.
 Activity 2: Building a model
• You will build a villin
model which
simulates the proper
folding of villin.

• “Snack” description
 Protein folding time scale
• Proteins self-assemble, i.e. fold,
amazingly quickly: some as fast as
a millionth of a second.

• While this time is very fast on a

person's timescale, it's remarkably
long for computers to simulate.
Why is protein folding difficult to
simulate on a computer?
• It takes about a day to simulate a nanosecond
(1/1,000,000,000 of a second) on a computer.

• Unfortunately, proteins fold on the tens of

microsecond timescale (10,000 nanoseconds).

• Thus, it would take 10,000 CPU days to

simulate folding -- i.e. it would take 30 CPU
years! That's a long time to wait for one result!
A Solution: Distributed Dynamics

• Dr. Pande’s group at Stanford University has

developed a new way to simulate protein folding by
dividing the work between multiple parallel processors
in a new way -- with a near linear speed up in the
number of processors. Thus, with 1000 processors, it is
possible to break the microsecond barrier and help
unlock the mystery of how proteins fold.

• The parallel processors are personal computers

connected to the web. The computational power of
these computers is used when they are in an idle state.
 Folding@Home
• Folding@Home 1.0 has been a success. During
the one year period from October 2000 to
October 2001, Dr. Pande’s groups was able to
computationally fold several small, fast folding
proteins, with experimental validation of our
method.

• They are now working to further develop their

method, and to apply it to more complex and
interesting proteins and protein folding and
misfolding questions.
 Folding@Home
 
• Everybody can help the project by
downloading and running our client software
on their computer

• For every computer that joins the project, there

is a commensurate increase in simulation
speed.

• Download the software now and be part of an

exciting research that can benefit
advancements in medicine and biology!
 Using the down time of your
computer connected to the web
• The Folding@Home
client (console or
screen saver) shows
real time
visualizations of the
protein simulations
being performed.
• The molecule drawn
is the current atomic
configuration ("fold")
of the protein being
simulated on your
computer.
 Suggested reading for
teachers and students
• Michael Crichton, Prey, Harper Collins,
2002
• How the cows turned mad, Maxime
Schwartz, University of California Press,
2003
• Jeremy Cherfas, The human genome,
Dorling Kindersely, 2002
• Mark Ratner & Daniel Ratner,
Nanotechnology, Prentice Hall
 Credits
• CPIMA provided leadership and
vision.
• Dreyfus Foundation provided
financial support.
• The Exploratorium in San Francisco
supported us a hands-on approach to
science philosophy.
Thank you !