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02foct29p1 - Harvard-MIT Division of Health Sciences and...

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Harvard-MIT Division of Health Sciences and Technology HST.508: Genomics and Computational Biology RNA2: Last week's take home lessons • Clustering by gene and/or condition • Distance and similarity measures • Clustering & classification • Applications • DNA & RNA motif discovery & search 1
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2 Protein1: Today's story & goals Protein interaction codes(s)? • Real world programming • Pharmacogenomics • Chemical diversity : Nature/Chem/Design • Target proteins : structural genomics • Folding, molecular mechanics & docking • Toxicity animal/clinical : SNPs : cross-talk
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3 Palindromicity 0.97 0.92 0.92 0.39 CompareACE score of a motif versus its reverse complement • Palindromes: CompareACE > 0.7 • Selected palindromicity values: Crp PurR ArgR CpxR
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Is there a code for protein interactions with DNA or RNA?
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5 Interactions of Adjacent Basepairs in EGR1 Zinc Finger DNA Recognition See Isalan et al., Biochemistry (‘98) 37:12026-12033
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6 Motifs: weight all 64 K a app Wildtype RSDHLTT RGPDLAR REDVLIR LRHNLET TGG 2.8 nM GCG 16 nM 2.5 nM TAT 5.7 nM AAA,AAT,ACT,AGA, AGC,AGT,CAT,CCT, CGA,CTT,TTC,TTT AAT 240 nM KASNLVS
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7 Phycoerythrin - IgG Combinatorial DNA-binding protein domains ds-DNA array Martha Bulyk et al Phage Combinatorial arrays for binding constants
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Ka apparent (association constant) 8
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9 DNA binding Fig (http://www.bmb.psu.edu/tan/tanlab_website/galler y/zif268dnajpg ) GCN4 fig (http://www.rtc.riken.go.jp/jouhou/image/dna- protein/all/small_N1ysa.gif Zn finger Textbook (wrong) Leu Zipper Textbook (wrong)
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A code for protein interactions with RNAs? See Wang et al. (2001) Expanding the genetic code of Escherichia coli. Science 292:498-500 10
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11 Protein1: Today's story & goals • Protein interaction codes(s)? Real world programming • Pharmacogenomics : • Chemical diversity : Nature/Chem/Design Target proteins : structural genomics Folding, molecular mechanics & docking • Toxicity animal/clinical : SNPs cross-talk
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12 Real world programming (3D + time) Perl exercises & central dogma: Bit I/O, syntax, memory, conditionals, loops, operators, functions, documentation. For real world interfaces add: Sensors & actuators Issues of feedback, synchrony, analog to digital to analog
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13 Scary proteins Anthrax P rotectve A ntigen (transport) E dema F actor L ethal F actor ( Nature Biotech 19:958 ) (http://arep.med.harvard.edu/pdf/Mourez01.pdf) HIV-1 Polymerase ApoE4 & Alzheimer’s Staph hemolysin Atherosclerosis (Net2)
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14 Protein programming time scales f- to nsec atomic motion µ - to msec enzyme turnover sec drug cell diffusion min transcription hr-day cell-cycle day circadian 17 years cicada 100 years aging
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15 What good are 3D protein structures? Depends on accuracy. See Baker Sali (2001) Science 294/5540/93/F1 &
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16 Stout TJ, et al. ure-based design of inhibitors specific for bacterial thymidylate synthase. Biochemistry. 1999 Feb 2;38(5):1607-17.
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