BORIS RUBINOV SUPERVISED BY: PROF. GONEN ASHKENASY BEN-GURION UNIVERSITY OF THE NEGEV, BEER-SHEVA,...

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Boris RubinovSupervised by: Prof. Gonen AshkenasyBen-Gurion University of the Negev, Beer-Sheva, IsraelFrom Structure to Function: Possible Implications of -Sheet Peptides to the Origin of Life01.12.13ILASOL 27th meeting Weizmann Institute of Science

1GoalsDesign and investigation of a new class of self - replicating peptides, based on folding into -sheet secondary structure.01.12.13 - ILASOL2

23DNAL.E. Orgel; G. von KiedrowskiRNAG. von Kiedrowski; G. F. JoyceAbiotic organic moleculesJ. Rebek; D. Philp; I.O. SutherlandPeptides helixM.R. Ghadri; J. Chmielewski; G. Ashkenasy

Dadon, Z., Wagner, N., and G. Ashkenasy, Angew. Chem. Int. Ed., 2008. 47(33)01.12.13 - ILASOLMinimal Self-Replication Systems

34Self-Replication by Peptides

-Helices:Long sequences: 28-40 a.aSpecific sequences2 layers of recognitionProduct inhibition-Sheet:Short sequence: 10-13 a.aSimple sequencesAssembly by H-bondsNo product inhibitionB. Rubinov, N. Wagner, H. Rapaport, and G. Ashkenasy, Angew. Chem. Int. Ed., 2009. 48.

01.12.13 - ILASOL4Prebiotic condensation of amino acids to -sheet peptides S.L. Miller; L.E. Orgel; A. BrackHigh structural stabilityC.M. Dobson; A. BrackSelf-propagation/replication and information transitionC.M. Dobson; C.P.J. Maury; H. MiharaEnantioselective PeptidesA. Brack; M. LahavHydrolysis/formation of oligoribonucleotidesB. Barbier, A. Brack5-Sheet Peptides (possible implications to the Origin of Life)

01.12.13 - ILASOLN. Wagner, B. Rubinov, G. Ashkenasy, ChemPhysChem, 2011, 12

H. Mihara et. al., Bioorg. Med. Chem., 2004I. Weissbuch, R. A. Illos, G. Bolbach, M. Lahav, Acc. Chem. Res. 2009, 425System Design -Sheet Peptides

01.12.13 - ILASOL6

Isenberg, H., K. Kjaer, and H. Rapaport, J. Am. Chem. Soc., 2006. 128(38)6Structural CharacterizationIn aqueous solution01.12.13 - ILASOL7AFM topography images of 1 and 2 fibrils (a and b respectively, 100 M), formed after 30 minutes of equilibration (z scale = 4 nm)

a

b

7From Structure to FunctionDesign of replication system 1

01.12.13 - ILASOL8

1189Kinetics Experiments of Replication System[E1]0=[N1]0= 25010 M; pH = 7; TCEP; 1 = [1]t [1]0

01.12.13 - ILASOL

116 M41M12M9M0M~100 - fold

B. Rubinov, N. Wagner, H. Rapaport, G. Ashkenasy Angew. Chem. Int. Ed., 2009. 48.9Full System MechanismTwo parallel processes

B. Rubinov, M. Matmor, N. Wagner, O. Regev, N. Ashkenasy, G. Ashkenasy, ACS Nano 2012, 6(9)Highlighted in Nature Nanotechnology 2012, 7, 54901.12.13 - ILASOL1010

Molecular mechanism of PRION replicationFor example: Sindi & Serio Curr. opin. Microbiol. 2009.Prions are infectious agents responsible for a variety of neurodegenerative disorders, including scrapie in sheep, bovine spongiform encephalopathy (BSE) in cattle, and new variant Creutzfeldt-Jacob disease (CJD) and kuru in humans.PrPSc = Scrapie form misfolded proteinReplication mechanismPrPc PrPScSynthesisE + N FPrPc + PrPScn PrPScn+1CatalysisE + N + Fn Fn+1PrPScn PrPSc1n+ PrPSc2nFragmentationFn F1n + F2nPrPScn / PrPSc PrPcDecayFn NT01.12.13 - ILASOL11From Structure to FunctionDesign of replication system 201.12.13 - ILASOL12

12Epimerization & Isomerization of E201.12.13 - ILASOL13

131401.12.13 - ILASOL[E--L]=[E--D]=30010 M; [N2]=60010 M; pH=7; Shaking @ 500-600 rpm

Kinetics Experiments of Replication SystemTemplate free reactions Background reactions141501.12.13 - ILASOLKinetics Experiments of Replication SystemTemplate assisted reactions Self-replication reactions

[E2]=[N2]=25010 M; MOPS buffer (0.2 M) pH=71516Summary of -Sheet ReplicationPeptides replication achieved using short & simple sequences.Peptide ligation (condensation of amide bond) in mild conditions (pH 7, r.t.) is plausible.The ligation reaction can be catalyzed by -sheet structures through self-replication process.The template-assisted reaction is regio- and stereo-selective.-Sheet structures may act as homochiral precursors in the origin of life.01.12.13 - ILASOL1617AcknowledgmentsProf. Gonen AshkenasyDr. Nathaniel WagnerDr. Riky Cohen-Luria Dr. Manickasundaram SamiappanDr. Jayanta NandaZehavit DadonInbal ShumacherLina ShepelevskiSamaa AlasibiDenis IvnitskiRakesh MukherjeeChiara GlionnaNadia LevinVered ZavaroTania DronovAnne Zebitz EriksenCollaborators:

Prof. Hanna Rapaport (GIXD)Dr. Vladimir VaiserDr. Shlomit Magidovich

Prof. Oren Regev (cryo-TEM)Dr. Einat RothEran Edri

Prof. Nurit Ashkenasy (AFM)Maayan Matmor

Dr. Yifat Miller (MD)Yoav RazTHANK YOU01.12.13 - ILASOL17