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  • 1. Videgames helping ScienceVideogames helping scientistsScience inVideogamesVideogames as Science popularizerTechnology inVideogames
  • 2. University of Washingtonhttp://fold.it/portal/
  • 3. ©2011NatureAmerica,Inc.Allrightsreserved.Crystal structure of a monomericretroviral protease solved byprotein folding game playersFiras Khatib1, Frank DiMaio1, Foldit Contenders Group, Foldit VoidCrushersGroup,SethCooper2,MaciejKazmierczyk3,MiroslawGilski3,4,Szymon Krzywda3, Helena Zabranska5, IvaPichova5,JamesThompson1,Zoran Popović2, Mariusz Jaskolski3,4 & David Baker1,6Following the failure of a wide range of attempts to solve thecrystal structure of M-PMV retroviral protease by molecularreplacement, we challenged players of the protein folding gameFoldit to produce accurate models of the protein. Remarkably,Foldit players were able to generate models of sufficient qualityfor successful molecular replacement and subsequent structuredetermination. The refined structure provides new insights forthe design of antiretroviral drugs.Foldit is a multiplayer online game that enlists players worldwide tosolve difficult protein-structure prediction problems. Foldit playersleverage human three-dimensional problem-solving skills to inter-act with protein structures using direct manipulation tools and algo-rithms from the Rosetta structure prediction methodology1. Playerscollaborate with teammates while competing with other players toobtain the highest-scoring (lowest-energy) models. In proof-of-concept tests, Foldit players—most of whom have little or no back-ground in biochemistry—were able to solve protein structure refine-ment problems in which backbone rearrangement was necessary tocorrectly bury hydrophobic residues2. Here we report Foldit playersuccesses in real-world modeling problems with more complex devia-tions from native structures, leading to the solution of a long-standingprotein crystal structure problem.Many real-world protein modeling problems are amenable to com-parative modeling starting from the structures of homologous pro-teins. To make use of homology modeling techniques in Foldit, weintroduced a new capability called the Alignment Tool, which allowsplayers to manually move alignments and thread their sequence ontothe structures of known homologs (Supplementary Fig. 1). PlayersStructure Prediction (CASP) experiment was an ideal venue in whichto test this. CASP is a biennial experiment in protein structure predic-tion methods in which the amino acid sequences of structures thatare close to being experimentally determined—referred to as CASPtargets—are posted to allow groups from around the world to predictthe native structure (http://predictioncenter.org/casp9/). Each grouptaking part in CASP is allowed to submit five different predictions foreach sequence. Foldit participated as an independent group duringCASP9 and made predictions for the targets with fewer than 165 resi-dues that the CASP organizers did not indicate as oligomeric. For targetswith homologs of known structure—the Template-Based Modelingcategory—Foldit players were given different alignments to templatespredicted by the HHpred server3 via the new Alignment Tool. Despitethese new additions to the game, the performance of Foldit playersover all CASP9 Template-Based Modeling targets was not as goodas those of the best-performing methods, which made better use ofinformation from homologous structures; extensive energy minimiza-tion used by Foldit players tended to perturb peripheral portions of thechain away from the conformations present in homologs.For prediction problems for which there were no identifiable homo-logous protein structures—the CASP9 Free Modeling category—Folditplayers were given the five Rosetta Server CASP9 submissions (whichwere publicly available to other prediction groups) as starting points,along with the Alignment Tool. Here all five starting models wereavailable, allowing players to use partial threading to combinedifferent features of the Rosetta models. In this Free Modelinga bFigure 1 Successful CASP9 predictions by the Foldit Void CrushersGroup. (a) Starting from the fourth-ranked Rosetta Server model (red) forc.Allrightsreserved.B R I E F COM MU N I CCrystal structure of a monomericretroviral protease solved byprotein folding game playersFiras Khatib1, Frank DiMaio1, Foldit Contenders Group, Foldit VoidCrushersGroup,SethCooper2,MaciejKazmierczyk3,MiroslawGilski3,4,Szymon Krzywda3, Helena Zabranska5, IvaPichova5,JamesThompson1,Zoran Popović2, Mariusz Jaskolski3,4 & David Baker1,6Following the failure of a wide range of attempts to solve thecrystal structure of M-PMV retroviral protease by molecularreplacement, we challenged players of the protein folding gameFoldit to produce accurate models of the protein. Remarkably,Foldit players were able to generate models of sufficient qualityfor successful molecular replacement and subsequent structuredetermination. The refined structure provides new insights forStructure Prediction (CASP) experiment was an idealto test this. CASP is a biennial experiment in protein sttion methods in which the amino acid sequences ofare close to being experimentally determined—referrtargets—are posted to allow groups from around the wthe native structure (http://predictioncenter.org/casp9taking part in CASP is allowed to submit five differenteach sequence. Foldit participated as an independenCASP9 and made predictions for the targets with fewedues that the CASP organizers did not indicate as oligomwith homologs of known structure—the Template-Bcategory—Foldit players were given different alignmenpredicted by the HHpred server3 via the new Alignmenthese new additions to the game, the performance oover all CASP9 Template-Based Modeling targets was those of the best-performing methods, which madinformation from homologous structures; extensive ention used by Foldit players tended to perturb peripheral
  • 4. http://folding.stanford.edu/English/HomePage
  • 5. animusDNA “memory”
  • 6. Ethics and Morals
  • 7. Ethics and MoralsNuclear fuel or nuclear weapons?Brain scanning or Big Brother?Climate saviour or climate disaster?Baby blessing or Brave New World?
  • 8. Technologyfirst DVD player PS2first Bluray player PS3Wiimote, 3D screensMS Kinect