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BIOTECHNOLOGY & YOU

Volume 9, Issue No. 1

Computers &Biotechnology

a magazine of biotechnology application in healthcare, agriculture, the environment, and industry

2 Computers and Biotechnology

BIOTECHNOLOGY & YOU

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Volume 9, Issue No. 1

Published by:The Biotechnology Institute

In Partnership with:Pennsylvania Biotechnology AssociationBiotechnology Industry Organization

Originally Developed as Your World/OurWorld by:The Pennsylvania Biotechnology AssociationThe PBA Educational CommitteeSnavely Associates, Ltd.

Editing by:The Writing Company, Cathryn M. Delude andKenneth W. Mirvis, Ed.D.

Design by:Snavely Associates, Ltd.

Illustrations by:Patrick W. Britten

Science Advisor:Laurence A. Weinberger, Esq.

The Biotechnology Institute is dedicated toenhancing the understanding of bioscience amonglay audiences and in fostering connections amongbioscience companies and universities. TheBiotechnology Institute thanks the PennsylvaniaBiotechnology Association and its educationcommittee under the leadership of Laurence A.Weinberger for developing this issue.

Your World describes the application of biotechnol-ogy to problems facing our world by bringingscientific discoveries to life. We publish an issue ondifferent topics each fall and spring. If you wouldlike information on subscribing for individual,teacher, or library sets, or if you would like tosponsor distribution in your area, contact theBiotechnology Institute. Some of the fourteen backissues are available.

For more information:Biotechnology Institute1524 W. College Avenue, Suite 206State College, PA 16801800-796-5806www.BiotechInstitute.org

Pennsylvania Biotechnology Association20 Valley Stream Parkway, Suite 265Malvern, PA 19355610-578-9220

Copyright 1999, BI. All rights reserved.

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P R O F I L E

Computers & Biotechnology

1

On the cover: Computers are helping us understand more about

our world by showing us the shapes of molecules and the

information contained in genes. This issue describes just a few of

the computer modeling techniques and bioinformatic systems that

provide a faster and more direct way of researching genetics and

drugs. These techniques are also advancing many diverse fields of

science, from agriculture to zoology. Today, all biotech research

depends on computers. Who knows what tomorrow will bring?

Hunting for Genes

Introduction:

A Graphic View of You!

SNPs and Chips

Viewing Molecules and Proteins

Every PictureTells a Story

A C T I V I T Y

John McAlister: Computer Modeler

Molecular Puzzles

12 Searching for Drugs

Credits:Data used to generate the protein images in this issue were obtainedfrom the Protein Data Bank (PDB): http://www.rcsb.org/pdb/

Page 3 and page 9: Neuraminidase (PDB ID: 1BJ1, N. R. Taylor et al.,J. Med. Chem. 41 pp. 798, 1998); Page 11: Hexokinase (PDB ID:1HKG, T. A. Steitz et al., Philos. Trans. R. Soc. London 293 pp. 43,1981); Page 11: Hemoglobin (PDB ID: 1ABW, K. S. Kroeger, C. E.Kundrot, Structure (London) 5 pp. 227, 1997)

Your World 3

Thirty years ago, students had it tough! They used manual

typewriters and whiteout for term papers. They made copies

with carbon paper instead of photocopiers. They used slide

rules instead of calculators. If they had access to a computer,

they used punchcards and programming language — there

were no graphics. Video and computer games

weren’t even science fiction yet. But now

computers have completely changed

they way you learn, work, and play!

A G R A P H I C V I E W O F

Computers have also changed the wayscientists conduct research. You canboil these changes down to two areas:handling enormous amounts of informa-tion and displaying this information invisual, graphic form. The same com-puter technology that makes realisticvideo games and special effects moviespossible is now at work in physics,chemistry, biology, ecology, populationstudies, epidemiology, agriculture, forestmanagement, archeology, anthropology,and more. This issue of Your Worldfocuses on how computers help us studythe world of genes, proteins, andmolecules in search of better medicinesand cures for diseases.

Your genes hold the secret to who youare. They play a major role in how

You!to handle the huge amount of informa-tion stored in genes. The marriage ofcomputers and genes is calledbioinformatics.

We are also using computer modelingto learn more about how life functionsat the molecular level. Sometimes thestraightforward information about agene’s DNA doesn’t provide enoughclues about its function. But if scien-tists can see the shape of the proteinthe gene produces, they might say,“Ah, ha! We see how it might interactwith other molecules of life.”

In this issue of Your World, you willlearn about how computers havecombined the fields of biology,genetics, and medicine to make ourworld more understandable, healthy,and safe.

Your World 3

you look, respondto your environment,

get sick, age, andmaybe even how you act. If

we could get a complete computer“printout” of your genes, it would showeverything you have in common withother living things, as well as every-thing that makes you unique. Youcould find out if you’re prone to aparticular disease so you could getpreventive treatments or cures. Youcould also learn which drugs mightwork best for you. To do such ananalysis, though, we need to compareyour genes to “standard” human genesand to variations of them. We alsomust understand the function of thesegene variations and the differentproteins they produce.

None of this would be possible withoutthe enormous power of computers.

First of all, we need computers


A Genetic Gold MineIn 1990, scientists began a united journeyto explore the gold mine of informationhidden in the human genome. “Genome”

refers to all the DNA on all thechromosomes. Scientists

called their effortthe Human

Knowing sequences of bases in thegenome is only half the story. Thesecond half is finding useful information– genes – within the genome. We haveabout 100,000 genes, but they make uponly about 10% of our genome.

To find and study genes, scientists firsthad to develop the new computers,programs, and data systems that havebecome known as bioinformatics.Computers allows us to store, organize,search, compare, and interpret enor-mous amounts of data. Without com-puters, genetic research would be likefinding a needle in a haystack, or usinga library without a catalog, or lookingfor specks of gold in “them thar hills.”

Data MiningScientists call the search for genes“data mining.” It is like digging for gold(a gene) among vast quantities of rock(the non-meaningful DNA that camou-flages the gene). Instead of using pickaxes, scientists use computer tools tosift through data.

built, the amino acid chain folds, twists,and turns to form a protein with hills,valleys, and ridges. These shapesdetermine how the protein interactswith other proteins and molecules –and these interactions are the basis ofmany biological processes. A smallchange in the DNA sequence of a genecan substitute one amino acid foranother in the protein, which may alterthe way a protein folds. This change inshape can affect the way the proteinfunctions, such as determining youreye color, your blood type, or whetheryou have a certain disease.

Genome Project. Their task would behard enough if there were just onehuman genome. But there are billions,one for each person! And each person’sgenome has three billion DNA bases.The result? An overwhelming numberof massive sequences, each too largeto comprehend.

PRIMER: GENES AND PROTEINPRIMER: GENES AND PROTEINPart of the secret of genes includesthe tale of how genes make pro-teins. A gene is a unique sequence(order) of DNA bases. (We refer tothe four chemical bases by theletters A, T, C, and G.) The sequenceof bases in a gene determines theorder of a chain of amino acids.Amino acids are small buildingblock molecules that we breakdown from the proteins in the foodwe eat. Each three-letter genetic“word” codes for one of 23 differ-ent amino acids in our bodies. Once


Your World 5

To complicate matters, all “words” inthe genetic language are only threeletters long. We could start reading inany of three positions:

1) gta cgc gct..

2) g tac gcgcta...

3) gt acg cgc tag...

Fortunately, we have some guidepoststo help us “read” DNA. For example,the “rock” sections of DNA usually startwith “GT” and end with “AG.” Thecomputer ignores these stretches,

clearing away some rock from the gold.Computers can identify signal se-quences for the beginning or end of agene, and look for clues about thefunction of a gene.

Working BackwardsAnother gene-mining tool worksbackwards to the genes themselves.The living cell knows exactly how to

separate gold from rock when making aprotein. The cell extracts the DNA

gold and translates it intomessenger RNA (mRNA).

Scientists extract themRNA and copy it

back into aDNA

sequence, called complementary DNA(cDNA), which corresponds to thegene. But it doesn’t have any rock, so itis easier to read. The computer cannow search for the gene and pinpoint itin the genome.

Finding Similar GenesWe have about 100,000 genes, and eachgene codes a unique protein. Thus, yourbody produces about 100,000 differentproteins. But many of those proteins aresimilar and belong to a large family.

Within each family, related proteinsperform similar functions, and theirgenes have similar sequences.

Scientists are using information aboutsimilar sequences to find more membersof a very important family that may helpus treat diseases: receptors. Receptors onthe cell’s surface receive messages, such

as hormones, from outside and send themessages inside. There may be thou-sands of different receptors. One groupof receptors interacts with about 60% ofall our current drugs. So far scientistshave identified about 250 members ofthis group, but they think there areabout two thousand. Finding them willhelp us develop new drugs.

To hunt for them, scientists use a familyprofile. All the receptors in this grouphave seven amino acid segments thatspan the cell membrane. (These particu-lar amino acids all like fat and don’t likewater, so they stick into the fatty parts ofthe cell membrane!) A computer searchfor DNA sequences that produce similarseven-segment proteins can track downmore members of this receptor group.

Let’s suppose the following “gene” liesburied in the DNA hillside:

Our “computer” brain can divide thisstring of letters into words. Try it! Butgenetic words are like metal oreintermixed with rock; they aresprinkled among other letters with noknown meaning:

These intermixed rocks make the taskof sorting out words much harder! Nowsuppose we use only four lettersinstead of the 26 in our alphabet – as isthe case with DNA:

wypdhfiwhshwcicomputerprogramshavemdoiweuernbeendesignedtolocatemeandorwwrcznxvouwingfulinformationinthelwurnwegkjeyongseriesofbasesequences

computerprogramshavebeendesignedtolocatemeaningfulinformationinthelongseriesofbasesequences

gtacgcgctagctagctaagctagatgcatgdctagcttcagaggaaattaccccaaatggtggactacatgtcagtagcaaatggccctagc

There are 5 billionpeople on earth,each having 3billion bases. Howmany bases is that?(5 x 109) x (3 x

109)= 15 x 1018 =15,000,000,000,000,000,000!

Keeping track of thisinformation is a task only computerscan handle.

THIN

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ABOUT THIS!!


SNPs and ChipsA Snip of IndividualityDo you know your blood type? Whether you belong to theA, B, or O blood group depends on a tiny genetic variationyou’ve inherited from your parents. The A blood group hasthis partial sequence: CGTGGTGACCCCTT. The O grouphas deleted one G base and has: CGTGGTACCCCTT. Thisgenetic difference codes different proteins that then pro-duce different antigens in your blood.

The ABO blood groups result from the most common type ofgenetic variation, single base changes. Scientists nicknamethis difference a SNP, pronounced “snip.” (The full name issingle nucleotide polymorphism: “poly” means many;“morph” means shape; and “nucleotide” is a DNA base.)

Each SNP is a minute fraction of your genome, but it canmake an enormous difference. It may determine whetheryou succumb to a disease or resist one. For example, a SNPin a gene called “apoE” can lead to Alzheimer’s disease. Acertain rare SNP in a receptor gene makes people immuneto HIV infection. SNPs may also explain why some peoplerespond well to drugs, some do not, and others have nega-tive side effects.

All in all, there may be three million SNPs buried in ourgenome. How can we find them all, much less understandtheir importance? Scientists are using computers to collectinformation about variations in the human genome andthen match tiny variations with subtle differences in diseasestates and drug responses.

Such work will take a lot of time and effort, but scientistsbelieve it will pay off. Drug companies may use SNP infor-mation to predict the effectiveness and side effects of a newdrug – before costly clinical trials. Doctors may use it whenprescribing drugs for patients, checking to see if a patient

has a particular SNP that makes a drug unsafe orineffective. We already have “contraindication” warn-ings on many drugs, but some people are still harmedby drugs. Bioinformatics could provide a more specificand accurate warning system for all of us.

Chips for Testing GenesOne tool to help scientists gather information about SNPs isthe DNA chip. You may have seen the tiny circuits on acomputer chip. Scientists use “photolithography” to createthese circuits. They shine light through differently pat-terned masks and expose the chip to chemicals in thosepatterns to create different circuits. This process is similarto screen art: You use one stencil for yellow paint on whitepaper and another pattern for blue paint to create a designof yellow, blue, green, and white.

Scientists use this technology to make DNA chips fortesting genetic variations in a sample. Instead of buildingup circuits, they build strings of DNA bases to creategenetic probes. Computers design grids of thousands ofprobes for different genetic variations. Scientists expose thechip to the DNA and/or RNA from a cell. The chip capturesany matching sequences in the sample. Beforehand, thegenetic material was tagged with a fluorescent molecule.When scientists shine a visible light on the chip, thecaptured genetic sequences glow. A computer matches theglowing sites on the chip to the layout of genetic probes.Then it can provide a readout of the genetic variationsfound in the sample cell.

Scientists are using such tools to develop genetic “profiles”of diseases. A profile shows the pattern of genes that areactive in a cell. Computers compare the profiles of normaland diseased cells so scientists can sort out the commongenetic features of a disease.

These disease profiles may help us identify the geneticcauses of a disease, diagnose complex diseases more accu-rately, and find new treatments or cures. Scientists will usethese profiles to test thousands of potential drug molecules.They will test the gene profile after a diseased cell is treatedwith each drug candidate. If a molecule changes a diseaseprofile to a healthy profile, it may make a good drug. TheNational Cancer Institute has profiled 60 types of cancer andscreened 70,000 possible drug molecules against them. Theyare now searching databases to see if any of the molecuesmight be effective cancer fighters.

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DNA chips, such as the array shown, contain manyvariations of genetic sequences and can help identifywhich genetic variations exist in a sample.

Your World 7

Bioinformatics can help scientists trace the Ice Maiden’s DNA to her people’sancestors — and descendants.

In 1995 an anthropologist was climbing the 20,700 foot Mt.Ampato in the Peruvian Andes Mountains when he found thefrozen mummy of a teenage girl. This “Ice Maiden” hadbeen sacrificed by Incan priests 500 years ago – perhaps tosatisfy a mountain god. The icy temperature preserved hertissues so well that scientists could extract DNA from her cells.Anthropologists study people’s ethnic and cultural roots, so

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The Ice Maiden

T G T C C A A A T G T G A C A A A C T G T G T C C A A A T G T G A C A A A C T G G G C T G A T A T G T G A C A C A C T G T C G A A A G A C G G G A T A A A C C T

Gene 1

Gene 2

Gene 3

Gene 4

This diagram shows the first 20 base sequences from four genes. Notice the high percentage of positions that have the samebases. How many positions have the same bases in all four genes? In three genes? The similarity among the base sequencesmeans they probably belong to a family of genes with common characteristics.

First 20 Sequences of Four Genes

they hoped the Ice Maiden’s DNA could help explain theorigins of the Incas.Scientists focused on two DNA sequences, each about 450bases long, from the mitochondria of her heart cells. (Mito-chondria are the parts of the cell that produce energy.)Mitochondrial DNA is passed down only from the mother, soit is possible to trace family lines through the maternal DNA.Already, scientists had used bioinformatics to compare themitochondrial DNA of Native Americans throughout Northand South America. Using this analysis, anthropologists tracedall these populations back to four original waves of Paleo-Indians who migrated from Asia into the Americas.One of the Ice Maiden’s mitochondrial DNA sequences showsthat she descended from one of these four waves, and it linksher to the Ngobe of Panama. There are also similarities togenetic patterns found in Taiwan and Korea, which supportsthe theory that Paleo-Indians originally came from Asia. Onesequence does not match any sequences found in anydatabase so far.Scientists do not yet have enough data on ancient populationsto trace the source of the Ice Maiden’s family. But anthropolo-gists have discovered three more frozen mummies in theAndes, so they will soon have more information about theIncas. Someday, scientists may use DNA comparisons to mapthe paths of early humans as we emerged from Africa andspread throughout the world.▼


Scientists are now using models tounderstand the molecules of life. Butmolecules and proteins are much moredifficult to model than planets and moons. Luckily, com-puters help us see these tiny structures.

Many biological functions are based on the interlockingshapes of molecules. For instance, antibodies recognizeinvading microorganisms by the shape of an antigenprotein on the microbe, and they are said to fit togetherlike a three-dimensional lock and key.

This lock and key analogy underlies many biochemicalreactions, including those involving two types of proteinsthat are very important in disease and drug treatment:enzymes and receptors. Proteins have an “active site” wherethey bind smaller molecules to themselves, causing achemical reaction. Part of the protein’s shape forms the lock,and part of the molecule forms a key that fits the lock. Formany proteins, this lock is a deep cleft or pocket in itssurface. Often, more than one kind of molecule has a keythat fits the protein’s lock.

Most of our existing drugs are molecules that interact withproteins, so having computers show us such shape interac-tions can help us develop more effective drugs. Scientists arekeenly interested in creating models of theproteins involved in health problems ranging

Can you imagine trying to understandthe solar system, or the seasons, or thecycles of the moon without a three-dimensional model showing the planetsrevolving around the sun? We are avisual species, and we are very good atunderstanding spatial relationships. Forthings that are either too large or toosmall for us to see, models helpus understand.

from diabetes to schizophrenia tomigraines. These models can give usinsights we could not get any other way.

Modeling ProteinsIf scientists know the structure of theprotein they want to study, they cancrystallize it and take an X-ray image ofit. The data from this image show therelative location of atoms in theprotein, similar to distances on a roadmap: If you had all the distancemeasurements from every town in thecountry, a computer could construct amap of the country. In the same way,

the computer can take the X-raycrystallography data, display thestructure in various ways, andeven rotate the views to revealall the shape’s features. (For asimple example, see thedifferent views of the caffeinemolecule on page 10. Aprotein’s structure is morecomplicated, like a tangledribbon of amino acid chains.)These rotating, 3-D viewsallow scientists to visualizehow a small moleculemight fit into abinding site on theprotein.

EveryPictureTells aStory


Your World 9

Scientists are comparing proteins fromdifferent species as well as from humans.This comparison is possible because thegenetic code is universal: it works thesame for worms as for us. Thesecomparisons are showing that evolutionis conservative. That is, new species

“recycle” genes from older species, so wehave many genes that are almost identical to

those in other species. These comparisons will helpevolutionary biologists and anthropologists draw a moredetailed family tree of the world.

THIN

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ABOUT THIS!!Your World 9

This is a stereo image of the neuraminidase protein. A stereo image allows you to see it in three dimensions. To do so,hold a sheet of paper against the page between the images, put the tip of your nose on the top edge, and look downon the images from a comfortable distance with the paper separating your eyes’ line of sight. Your brain will fuse theimage, but it may take some practice. You can practice on the simpler image of the caffeine molecule (#7) on the nextpage. Depending on your eyesight, you may need a longer piece of paper. If so, tape two pieces together.

A New Flu Drug

Watson and Crick Model: James Watson and Francis Crickdiscovered the structure of the DNA molecule in 1953, but theycould only represent it with mechanical parts. Today, computerscan represent molecules more realistically.

This computer-generated image shows a molecule bound to neuraminidase, anenzyme that allows the influenza (flu) virus to reproduce and infect you. Scientistsused this image to identify the cleft in the enzyme and to study the shape of themolecule that naturally binds to it. When this molecule binds, it breaks apart,allowing the virus to replicate. Using techniques discussed in the next article,scientists had the computer make modelsof other molecules that would fit into thecleft and not break apart. Next, theysynthesized (made in the laboratory)several molecules that fit the bill and testedthem. They used the most effective of thesemolecules in a new inhaler, which hasbeen approved as a drug. ▼

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Caffeine 7Do you want to see themolecule in three-dimensions?To fuse these images, followthe instructions for theneuraminidase protein on theprevious page.

Caffeine 3To simplify the display, theatoms and bonds are shownas tubes.

Caffeine 1This two-dimensional imageshows the relationship of atomsin the caffeine molecule. Atomsare represented by their firstletter (C=carbon, H=hydrogen,N=nitrogen, O=oxygen). Thechemical bonds between atomsare drawn as single, double, ortriple lines to indicate the typeof bond.

Caffeine 2This model represents eachatom as a ball and the connect-ing bonds as sticks. Differentcolors represent the atom types.(C=white, H=light green, O=red,N=blue.)

Viewing the Caffeine Molecule

Caffeine 4For a more realistic model, thecomputer represents the atomsas spheres with radii corre-sponding to atom size.

Caffeine 5&6The computer rotates the image to reveal that most of the atomsof the molecule lie in one plane.

To see how computers can represent molecular shapes, consider these modelsof the relatively simple molecule, caffeine.

Your World 11

Viewing Proteins

HemoglobinThis image represents the four chains of agenetically modified hemoglobin molecule asribbons. The atoms of the four heme groups thatbind oxygen are shown as spheres with an ironatom in the middle.

Hexokinase 2This model represents the protein as a ribbonshowing the chain of amino acids. We can followthe twists and turns of the protein’s folded form.

Hexokinase 1This model represents the hexokinase protein asspheres. The amino acid chain can not be distin-guished, but you can see the deep cleft “lock” atthe top center where the glucose “key” binds.

From such computer images,scientists are learning aboutthe interaction of specificshapes and how to design newmolecules that might interactwith these proteins.

Larger molecules, such as proteins, can be displayed in similar ways. Let’s take a look at the hexokinaseprotein, which binds to glucose (a sugar), and the hemoglobin molecule, which has four subunitsthat bind oxygen in your blood.


DRUGSFinding Similar MoleculesSuppose you know of a molecule thatbinds to a protein in a way thatpartially treats a disease. Perhaps,however, that molecule doesn’t make agood drug. (It may interact weakly, orcan’t get into a cell, or has unwantedside effects, or also interacts withanother protein in a harmful way.)Perhaps another molecule could bindto the same protein but work better.How do we find it? Traditionally,scientists tried to change the molecule’sstructure to mimic other drugs – orthey used the old hit-or-miss, trial-and-error method. Sometimes this works.But surely it also misses molecules.

One way to expand the search is toteach a computer to analyze compli-cated shapes. We humans recognizeshapes very quickly. We immediatelyknow the difference between a cat anda dog. But can a computer tell thedifference? Both animals have a head,two eyes, a nose, a body, four legs, anda tail. How could a computer distin-guish two breeds of dogs – a task that iscloser to the problems of drug discov-ery? Here are some methods scientistshave developed.

Ping Pong BallLet’s pretend you want to analyze aparticular dog’s shape. You can use aping pong ball as a probe and roll it overthe entire surface of the dog. At eachpoint on the surface, a computerrecords the exact location of the ball ona three-dimensional grid. The entire setof coordinates (X, Y, Z) of the ball in thegrid represents the dog’s shape.

In the same way, a computer traces amolecule in a three-dimensional grid,measures the location of a small probemolecule when it bumps up againstthe larger molecule and records thecoordinates. This is one method called“quantitative structure activityrelationship” or QSAR. We can use itto record the shape of several mol-ecules that we know “lock” to acertain protein andthen ask the com-puter to search for a“key” feature that allthose molecules share.


Searching for

Your World 13

Then scientists can search for othermolecules with the same feature.Scientists used a QSAR approach indeveloping the new antibacterial drugnorfloxacin, the Alzheimer’s treatmentdonepezil (AriceptTM), and the mi-graine drug zolmitriptan (ZomigTM).

The Animal’s DenAnother approach allows us to guessthe shape of the protein’s binding siteby examining the molecules that bindto it. What shapes do these moleculeshave in common? What can that tell usabout the protein’s “lock” (bindingsite)? Scientists call this approach the“pharmacore” method, and it is liketrying to define the shape of a den byexamining the animals that fit in it. Ifthey are all long and thin, the den isprobably narrow and deep. Once youhave modeled the shape of theprotein’s “den” (or “lock”), you canlook for molecules that have a “key”that would fit it. These molecules mayall have quite different chemicalproperties, but they share a similar“key” for the same protein.

Finding Different MoleculesThe ping pong ball and animal’s denapproach only get us so far in oursearch for new molecules, though.Suppose you want to find moleculesthat are different from those you havestudied? Perhaps none of the knownmolecules interacts in just the rightway with a protein involved in adeadly disease. In that case, you maywant to combine different moleculestogether to make new compounds.

This method, called “combinatorialchemistry,” allows scientists tosynthesize millions of new com-pounds. It is like choosing all possiblecombinations from a Chinese restau-rant menu: an entry from column Acombined with each meat option fromcolumn B; the second entry from Acombined with each option from B,and so on. If each column had tenthousand options, there are 100million (104 x 104) possible combina-tions. Maybe one of them is just thenew drug you want to find...

Now the trick is to screen thosecompounds to see if any interact with

the disease protein. But there are somany compounds to test – even usingthe robots that are now common inlabs! And many compounds havealmost identical shapes and biologicalactivity. Scientists would like to testonly those with significantly differentshapes and – probably – differentactivities. Computers are helping weedout the similar shapes, so scientists canconcentrate on representatives fromdifferent families of shapes. Then, ifthey find one promising molecule, theycan study its other family members.

Alternatively, they can use thesemethods to look for molecules withshapes similar to one they know, inorder to develop variations on asuccessful drug theme. That’s hownew alternatives to the antidepressantdrug fluoxetine (Prozac®) werecreated; scientists looked for mol-ecules with similar “keys” to thatwhich allows the drug molecule tointeract with chemicals in our brains.

FragmentsThe most common way to sortmolecules is to break them intofragments, like breaking the shape of a

dog down into nose, tail, ears, legs,etc. Then, a computer represents thepattern of those fragments as “bitstrings.” For each possible fragment, itassigns a “1” or a “0” to show if thefragment is present to create a stringlike this: 0001001111011010. Thenthe computer compares millions of bitstreams. Molecules with similar stringsmay have similar shapes and bindingproperties, so computers can sortmolecules into families. Scientists canuse these families either to concen-trate on differently shaped moleculesor to isolate members of one family.

Virtual LibrariesComputerized “virtual libraries” storethe shapes of larger molecular frag-ments. Computers then “cook up” allthe possible shape combinations inthe Chinese menu columns and pointout those “meals” that are similar anddifferent. Once scientists identifymolecules of interest, they cansynthesize and test them. Alterna-tively, the computer can model themolecule’s structure and superimposeit on the protein to see if it fits.

Fragments: The molecule on the top row is broken down into some of the possible overlapping fragments, which are shownin the second row. The third row shows a bit string where these fragments are represented as a “1”. (The “H” (hydrogen)atom doesn’t affect the activity of the molecule, so H3C-CH, CH-CH2, and CH2-C all produce the same fragment, C-C.)

Your World 13

Molecule

Fragments

Bit String

C

H

H

H H

H H H H H

H

H C C C C N

O O

0 0 0 0 0 0 0 0 0 0 0 0 0 01 1 1 1 1 1


Pro

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:John McAlister: Computer Modeler

verymorningJohn

McAlister tucks

John McAlister wrote some of the first computer modeling software in the 1980s. Someof his early modeling techniques are still alive and well in the biotech industry.

Ehis tie into hisshirt, puts hiscomputer in his

backpack, and rides his motorcycle towork. He started riding motocycles asa graduate student when it was theonly transportation he could afford.Now he takes one on cross countrycamping and backpacking trips withhis sons, looking for freedom andadventure. John finds the same senseof adventure and beauty in science.Ever since he was inspired by his highschool science teachers, John hasenjoyed the “excitement of discoverythat science is all about.”

As an undergraduate John studiedchemistry and mathematics at TarletonState College in Texas. After graduatingin 1971, he entered a Ph.D. program atthe University of Wisconsin and almostbecame a synthetic organic chemist.But the biochemistry department hadX-ray crystallography equipment, andJohn started analyzing the structure ofmolecules and proteins. Growingbacterial cell cultures from which toisolate the materials left a lot of idletime. John used it wondering whethermathematics and computers couldpredict the structures the moleculeswould assume. There were no suchprograms at the time, so John startedwriting his own.

At that time, X-ray crystallographydata consisted of large tables withnumbers. Graphing this raw datameant tediously drawing lines onplastic sheets and then stacking themup to give a sense of the three dimen-sional structure. Mechanical models(such as the one shown with Watsonand Crick on page 9) were con-

structed by matching parts to themolecule image on the stacked sheets.Again, John thought there must be abetter way.

Assembling parts from different compa-nies, John built one of the first molecu-lar graphic systems in the world. Hewrote the software to teach the com-puter how to display the numerical dataas an image.

In 1980 John moved to WashingtonUniversity in St. Louis to writesoftware for a computer graphicssystem to be given to 16 universitybiochemistry departments. This workled to a job as principal programmerat a new local company, Tripos, Inc.,which was starting to develop model-ing hardware and software. He oftenworked a programmer’s typical 24hour day to get the programs right.Eventually John became a manager sothat, as he puts it, he could “monitorwho touched his code.”

Today, many of those programs arestill used as the basis of high techsoftware. John is now president ofTripos, which has become one of theworld’s premier suppliers of moleculargraphics software to the biotechnologyindustry. John likes managing ascientific company and finding theresources to help creative peopleachieve their ideas. As for the futureof molecular modeling and analysis,John believes people are just begin-ning to understand the power ofvisualizing and mathematicallyanalyzing the information extractedfrom molecular data and the relation-ship among numbers.

Most of all, John hopes that students oftoday will share the excitement ofdiscovery on new scientific frontiers andappreciate that “science is a beautifulway to understand the world.”

Your World 15

How good are you at hunting for genesand matching keys to locks? Here area few activities to test your skills.

Gene HuntingThe sequence of letters on thebottom right contains a gene startingwith ATATTAG and ending withCCTTAT. Can you find it? Whatstrategies might help you find thesequence? Once you’ve found thebeginning and end of the gene, youcan sequence the entire gene!

Gene ProbingA gene probe can quickly find amatching part of a DNA sequence.Trace the “probe” at the right of thepage, including the separating lines,and then cut out the tracing. Thisprobe matches part of the sequenceshown on the diagonal. Each shape onthe probe must fit exactly into itscounterpart in the sequence, sincecomplementary DNA base pairs fittogether like puzzle pieces. Time howlong it takes you to find the probe’smatch.

5 seconds = genius gene finder;

10 seconds = average genefinder;

>15 seconds = you need acomputer!

IACTIVITY:Molecular Puzzles

CGATCGATATCGCTATACGATCGTAGGCTACCCTGCATCTATCGATCTATCGGGGATCGTATGCAT

GCAGGATCATGCTAAGCTAAGCATGCTACGCGTAT G T G C TAT G C A G TA G A G T C G A G C TA ATAT TA G TCGACTGTGAGCGACTGATGCTAGCTACGCTAGGGC C C TATAT G C TA AT C G G C TAT T C G AT TA G C TA CC G C T A C G T A T C T G T A T T C G A G G A G A C T CTTCCTGATAATCAGCTATGAAACCCCTATCTATCG C TAT C C C T T AT T C A G C G TAT G C TA A G C TATC G TAT C TA C G G TA AT TAT TAT T C A G C TAT C TAG C G C T A T C G C G C G A T T A A T T T G C T A T G A T AATA C G TATATA A AT G C T G AT C G TAT G C TA C G C TA T G C T A A G T G C T A C C G T C G T A C G G A C T G A

Molecular ModelingUse ping pong balls, Styrofoam balls,or similar round objects and someglue to construct a three dimensionalmodel of the caffeine shown on page10 of this issue.

Rotate the model to match thecomputer generated viewpoints.

• What can you learn from seeingthe model in three dimensions?

Caffeine interacts with certain pro-teins/receptors in your body.

• How would you describe the“key” shape of thecaffeine molecule?

Find the beginning and end of thegene in this sequence.

Use the probe to findits complementon thissequence.

• What does the shape of thiskey tell you about the “lock”(binding cleft) in the protein/receptor?

Your World 15

ACTIVITY:


Dear Students and Teachers:

We are delighted to provide you with this copy of Your World.The issue highlights the convergence of two importantareas of technology and illustrates how they enable new

discoveries, products, and services. This is the fifteenth Your World issuepublished over the past eight years on various topics in biotechnology.

This issue is an important milestone because it marks the movement ofYour World’s publication from the Pennsylvania BiotechnologyAssociation (PBA) to a new home within the Biotechnology Institute.The Biotechnology Institute has been formed by the BiotechnologyIndustry Organization and PBA to create a new national institute focusedon biotechnology education. The Institute will continue publishing YourWorld for an expanded national and international audience and willintroduce other biotechnology education initiatives.

For more information on the Institute, to look at or order previousissues, or to let us know your thoughts, please visit our web site atwww.biotechinstitute.org. The next issue of Your World will addressBiotechnology and AIDS.

The Biotechnology Institute thanks our founding sponsors, whosegenerous support has launched the Institute and made this issue of YourWorld possible.

Sincerely,

Jeff DavidsonDirector of Bioscience EducationBiotechnology Institute

Thank You!

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