Transcript To Fold or Not To Fold

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
prehistoric discovery, is
very widely distributed
in nature. It is found in
abundance in the sun,
stars, comets, and
atmospheres of most
planets.
• Carbon is the source of
energy for life through
carbohydrates, just like
a burning log is a
source of energy to a
cold room.
Atomic number 6
Atomic Symbol C
Atomic mass
12.011 u
Electron
Configuration
[He]2s22p2
Vocabulary: Hydrogen
• (Greek: hydro, water,
and genes, forming)
Hydrogen is the most
abundant of all elements
in the universe.
• The heavier elements
were originally made
from Hydrogen or from
other elements that
were originally made
from Hydrogen.
• Used in rocket fuel.
Atomic
number
1
Atomic
symbol
H
Atomic mass
1.0070 u
Electron
Configuration
1s1
Vocabulary: Oxygen
• Greek: oxys, sharp, acid,
and genes, forming; acid
former) Oxygen is the
third most abundant
element found in the sun.
Oxygen is vital to the
respiration of living
organisms.
• Oxygen is responsible for
the bright red and yellowgreen colors of the Aurora.
• Essential element for
combustion (i.e. burning).
Atomic
number
8
Atomic
symbol
O
Atomic mass
15.9994 u
Electron
Configuration
[He]2s22p4
Vocabulary: Nitrogen
• (Latin Nitrum, Greek.
Nitron, native soda; genes,
forming)
• Nitrogen gas (N2) makes
up 78.1% of the Earth’s
air, by volume.
• Nitrogen is found in all
living systems as part of
the makeup of biological
compounds.
• Ammonia (NH3) is the
most important
commercial compound of
nitrogen, with a very
pungent smell, used in
cleaning supplies.
Atomic
number
7
Atomic
symbol
N
Atomic mass
14.00674
Electron
Configuration
[He]2s22p3
Vocabulary: Sulfur
• (Sanskrit, sulvere; Latin
sulpur) Known to the
ancients; referred to in
Genesis as brimstone.
• Sulfur occurs native in the
vicinity of volcanoes and hot
springs.
• It is widely distributed in
nature in various minerals
(iron pyrites, galena,
sphalerite, cinnabar, stibnite,
gypsum, epsom salts,
celestite, barite, etc.)
• Sulfur is found in meteorites.
Atomic
number
16
Atomic
symbol
S
Atomic mass
32.6
Electron
Configuration
[Ne]3s23p4
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
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.
Rubber tree
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 "misfold") 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 !