02foct29p1

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

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Unformatted text preview: 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 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 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 Is there a code for protein interactions with DNA or RNA? 5 Interactions of Adjacent Basepairs in EGR1 Zinc Finger DNA Recognition See Isalan et al., Biochemistry (98) 37:12026-12033 6 Motifs: weight all 64 K a app ildtype SDHLTT GPDLAR EDVLIR RHNLET 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 ASNLVS 7 Phycoerythrin - 2 IgG Combinatorial DNA-binding protein domains ds-DNA array Martha Bulyk et al Phage ombinatorial arrays for binding constants Ka apparent (association constant) 8 9 DNA binding ig http://www.bmb.psu.edu/tan/tanlab_website/galler /zif268dna g GCN4 fig (http://www.rtc.riken.go.jp/jouhou/image/dna- protein/all/small_N1ysa.gif Zn finger Textbook (wrong) Leu Zipper Textbook (wrong) A code for protein interactions with RNAs? See Wang et al. (2001) Expanding the genetic code of Escherichia coli. Science 292:498-500 10 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 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 13 Scary proteins nthrax 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 & Alzheimers Staph hemolysin Atherosclerosis (Net2) 14 Protein programming time scales f- to nsec atomic motion - to msec enzyme turnover sec drug cell diffusion min transcription hr-day cell-cycle day circadian 17 years cicada 100 years aging 15 What good are 3D protein structures?...
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02foct29p1 - Harvard-MIT Division of Health Sciences and...

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