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    To Fold Or Not To Fold?An exploration of

    the exciting world

    of protein folding forhigh school chemistryor biology teachersand students.

    Claudia Winkler and Gary Benz

    Animation of the folding of

    villin, a well known protein

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    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 theconcepts we are introducing in theslides ahead might be clearer.

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    Vocabulary: Amino-Acid Amino-acids are the buildingblocks of proteins.

    They are characterized bythe presence of a carboxylgroup (COOH) and an aminogroup (NH3) attached to thesame carbon (called alphacarbon).

    The letter R representssuccinctly the rest towhich the amino-acid groupis attached.

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    Vocabulary: Chemical Bonds Except for noble gases which have achieved the state ofnirvana for their atoms, i.e. they have a complete outer

    shell of electrons, all other elements in nature pair up withother elements to complete their outer shell. This process iscalled chemical bonding.

    Bonds most relevant to organic chemistry are: covalentbonds and hydrogen bonds.

    Covalent bonds are characterized by sharing of electronsbetween the atoms bonding with each other to form amolecule.

    Hydrogen bonds keep together polar molecules, i.e. moleculeswhich have uneven distribution of electric charge.

    Hydrogen bonds can also occur between part of the samepolymer when there is charge polarity between different partsof the polymer.

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    Vocabulary: Carbon (Latin: carbo, charcoal)

    Carbon, an element ofprehistoric discovery, isvery widely distributedin nature. It is found in

    abundance in the sun,stars, comets, andatmospheres of mostplanets.

    Carbon is the source ofenergy for life throughcarbohydrates, just likea burning log is asource of energy to a

    cold room.

    Atomic number 6

    Atomic Symbol C

    Atomic mass 12.011 u

    ElectronConfiguration

    [He]2s22p2

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    Vocabulary: Hydrogen

    (Greek: hydro, water,and genes, forming)Hydrogen is the mostabundant of all elements

    in the universe.

    The heavier elementswere originally madefrom Hydrogen or fromother elements thatwere originally madefrom Hydrogen.

    Used in rocket fuel.

    Atomicnumber

    1

    Atomicsymbol

    H

    Atomic mass 1.0070 u

    ElectronConfiguration

    1s1

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    Vocabulary: Oxygen Greek: oxys, sharp, acid,

    and genes, forming; acidformer) Oxygen is thethird most abundantelement found in the sun.Oxygen is vital to therespiration of livingorganisms.

    Oxygen is responsible for

    the bright red and yellow-green colors of the Aurora.

    Essential element forcombustion (i.e. burning).

    Atomicnumber

    8

    Atomic

    symbol

    O

    Atomic mass 15.9994 u

    ElectronConfiguration

    [He]2s22p4

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    Vocabulary: Nitrogen (Latin Nitrum, Greek.Nitron, native soda; genes,

    forming) Nitrogen gas (N2) makes

    up 78.1% of the Earthsair, by volume.

    Nitrogen is found in allliving systems as part ofthe makeup of biologicalcompounds.

    Ammonia (NH3) is the

    most importantcommercial compound ofnitrogen, with a verypungent smell, used incleaning supplies.

    Atomicnumber

    7

    Atomicsymbol

    N

    Atomic mass 14.00674

    ElectronConfiguration

    [He]2s22p3

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    Vocabulary: Sulfur (Sanskrit, sulvere; Latinsulpur) Known to the

    ancients; referred to inGenesis as brimstone.

    Sulfur occurs native in the

    vicinity of volcanoes and hotsprings.

    It is widely distributed innature in various minerals(iron pyrites, galena,

    sphalerite, cinnabar, stibnite,gypsum, epsom salts,celestite, barite, etc.)

    Sulfur is found in meteorites.

    Atomicnumber

    16

    Atomicsymbol

    S

    Atomic mass 32.6

    ElectronConfiguration

    [Ne]3s23p4

    Yellowstone hot springs

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    Vocabulary: Proteins Proteins are necklaces of amino acids, i.e. long chain

    molecules. Proteins are the basis of how biology getsthings done.

    As enzymes, they are the driving force behind all ofthe biochemical reactions which makes biology work.

    As structural elements, they are the main constituentof our bones, muscles, hair, skin and blood vessels.

    As antibodies, they recognize invading elements andallow the immune system to get rid of the unwantedinvaders.

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    Vocabulary: (Protein) Folding Proteins are formed by unique sequences of

    amino-acids. However, only knowing thesequence tells us little about what the proteindoes and how it does it.

    In order to carry out their function (forinstance as enzymes or antibodies), proteinsmust take on a particular shape, also known

    as a "fold." Thus, proteins are truly amazingmachines: before they do their work, theyassemble themselves! This self-assembly iscalled "folding."

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    Vocabulary: Polymer Polymers are chemical compound

    with high molecular weight consistingof a number of structural units (calledmonomers) linked together bycovalent bonds.

    A structural unit is a group havingtwo or more bonding sites.

    Many polymers occur in nature, suchas silk, cellulose, caoutchouc (latex),

    which is natural rubber coming fromthe rubber tree, and proteins. Manyothers are man made (such asplastic), foam.

    Rubber tree

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    Vocabulary: Residue

    When amino acids connect with eachother to form a a specific protein, theydo so through a special kind of covalentbond that is called peptide bonds.

    In the formation of the bond, water isreleased. What remains is called a

    residue. Residues are the beads of thenecklace we introduced before.

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    Vocabulary: Synthesize To synthesize means to bring together. In

    chemistry it means to make a product from otherproducts.

    For instance A+B -> C means that element A isadded to element B to synthesize element C.

    Since the incredible development of Organic

    Chemistry in the 1900s, thousands of newcompounds have been synthesized, in the fieldsof textiles, building materials, plastic, paints,cosmetics, etc.

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    Vocabulary: Villin Villin is a protein thatgives structure tointestinal villi (shown inthe model to the right).

    Intestinal villi augmentthe surface of theintestine to increasefood absorption.

    However intestinal villineed to be stabilized,to add rigidity.

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    Why Villin? We chose villin as a model for

    protein folding.

    Villin is a well known proteinwhose folding processes have been

    studied and are understood amongthe scientific community.

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    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.

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    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.

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    Form determines function Suppose you have some molten iron. You

    may turn it into nails, hammers, wrenches,etc. What makes these tools different fromeach other is their form (i.e. their shape andstructure)

    Similarly proteins, though basically beingbuilt as similar chains of amino acids, very

    rapidly fold onto their own correct form, soas to be able to carry out the function that isassigned to them

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    Folding is critical

    When proteins do not fold correctly (i.e. they "mis-fold") there can be serious effects, including manywell known diseases, such as Alzheimer's, mad cowdisease (also known as Creutzfeldt-Jakob disease,prions, bovine spongiform encephalopathy, scrapie)

    and Parkinson's disease.

    Understanding protein folding is critical in themedical and clinical professions and as such it isthe subject of extensive research.

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    Villin folds

    Immediately after the villinpolymer is synthesized, it starts tofold over itself to form a perfectly

    defined geometrical structure.

    There is only one correct shapethat villin can fold into to perform

    its biological actions.

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    Villin model To represent folding in villin, we

    have built a model.

    The purpose of this model, to bedisplayed on the floor of the

    Exploratorium, is to simulate thecorrect folding of villin.

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    Activity 2: Building a model You will build a villin

    model which

    simulates the properfolding of villin.

    Snack description

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    Protein folding time scale

    Proteins self-assemble, i.e. fold,amazingly quickly: some as fast asa millionth of a second.

    While this time is very fast on aperson's timescale, it's remarkably

    long for computers to simulate.

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    Why is protein folding difficult tosimulate on a computer?

    It takes about a day to simulate ananosecond (1/1,000,000,000 of a second)on a computer.

    Unfortunately, proteins fold on the tens ofmicrosecond timescale (10,000nanoseconds).

    Thus, it would take 10,000 CPU days tosimulate folding -- i.e. it would take 30 CPUyears! That's a long time to wait for oneresult!

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    A Solution: Distributed Dynamics

    Dr. Pandes group at Stanford University hasdeveloped a new way to simulate protein folding bydividing the work between multiple parallelprocessors in a new way -- with a near linear speedup in the number of processors. Thus, with 1000processors, it is possible to break the microsecondbarrier and help unlock the mystery of howproteins fold.

    The parallel processors are personal computers

    connected to the web. The computational power ofthese computers is used when they are in an idlestate.

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    [email protected] [email protected] 1.0 has been a success. During

    the one year period from October 2000 toOctober 2001, Dr. Pandes groups was able to

    computationally fold several small, fast foldingproteins, with experimental validation of ourmethod.

    They are now working to further develop theirmethod, and to apply it to more complex andinteresting proteins and protein folding andmisfolding questions.

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    [email protected] Everybody can help the project bydownloading and running our client softwareon their computer

    For every computer that joins the project,there is a commensurate increase insimulation speed.

    Download the software now and be part of anexciting research that can benefitadvancements in medicine and biology!

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    Using the down time of your

    computer connected to the web The [email protected] (console orscreen saver) shows

    real timevisualizations of theprotein simulationsbeing performed.

    The molecule drawnis the current atomic

    configuration ("fold")of the protein beingsimulated on yourcomputer.

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    Suggested reading for

    teachers and students Michael Crichton, Prey, Harper Collins,

    2002

    How the cows turned mad, MaximeSchwartz, University of California Press,2003

    Jeremy Cherfas, The human genome,

    Dorling Kindersely, 2002 Mark Ratner & Daniel Ratner,

    Nanotechnology, Prentice Hall

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    Credits CPIMA provided leadership and

    vision.

    Dreyfus Foundation providedfinancial support.

    The Exploratorium in San Franciscosupported us a hands-on approachto science philosophy.

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    Thank you !