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BarMap & SundialsWrapper advanced RNA folding kinetics Stefan - - PowerPoint PPT Presentation

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BarMap & SundialsWrapper advanced RNA folding kinetics Stefan Badelt Institute for Theoretical Chemistry Theoretical Biochemistry Group stef@tbi.univie.ac.at February 17, 2015 1 Outline BarMap.pm & SundialsWrapper.pm Two

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SLIDE 1

BarMap & SundialsWrapper

advanced RNA folding kinetics Stefan Badelt

Institute for Theoretical Chemistry Theoretical Biochemistry Group stef@tbi.univie.ac.at

February 17, 2015

1

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SLIDE 2

Outline – BarMap.pm & SundialsWrapper.pm

Two libraries . . .

  • BarMap.pm

– interface to RNA folding kinetics on static landscapes – kinetics on time-varying energy landscapes

  • SundialsWrapper.pm

– solving arbitrary CRNs using the Sundials CVODE C-library

RNAsubopt barriers treekin Sundials CVODE

SEQUENCE

SundialsWrapper.pm

1 100 10000 1e+06 1e+08 Time/a.u. 0.2 0.4 0.6 0.8

BarMap.pm

1 100 10000 1e+06 1e+08 Time/a.u. 0.2 0.4 0.6 0.8

2

slide-3
SLIDE 3

Outline – BarMap.pm & SundialsWrapper.pm

Two libraries . . .

  • BarMap.pm

– interface to RNA folding kinetics on static landscapes – kinetics on time-varying energy landscapes

  • SundialsWrapper.pm

– solving arbitrary CRNs using the Sundials CVODE C-library

. . . and many tools:

  • BarMapSimulator.pl

– simulations on time-varying energy landscapes

  • interkin.pl

– kinetics of (multiple) pairwise interacting RNAs

  • transkin.pl

– co-transcriptional folding of long RNA molecules

  • . . .

2

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SLIDE 4

BarMap library

  • BarMapSimulator.pl

– kinetics on time-varying energy landscapes

RNAsubopt barriers

treekin

SEQUENCE

BarMap.pm

SEQUENCE

5000 10000 15000 20000 25000 0,2 0,4 0,6 0,8 1

time

  • ccupancy

Ivo L. Hofacker, Christoph Flamm, Christian Heine, Michael T. Wolfinger, Gerik Scheuermann, and Peter F. Stadler, BarMap: RNA folding on dynamic energy landscapes, RNA, (2010) 3

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SLIDE 5

BarMap and co-transcriptional folding

500 1000 1500 2000 2500 0,2 0,4 0,6 0,8 1

4

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SLIDE 6

BarMap and co-transcriptional folding

0,1 0,2 0,3 0,4 0,5 0,6 0,7 0,8 0,9 1 1,1 1,2 1,3 Time [seconds] 0,2 0,4 0,6 0,8 1 Population Density

BarMap Simulation

co-transcriptional folding

4

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SLIDE 7

BarMap including ligand interactions

x x

  • 28.0
  • 26.0
  • 24.0
  • 22.0
  • 20.0
  • 18.0
  • 16.0
  • 14.0
  • 12.0
  • 10.0
  • 8.0
  • 6.0
  • 4.0
2.1 2.2 3.7 6.1 3.5 1.6 2.2 3.4 3.3 2.8 3.9 2.8 3.6 2.6 1.4 2.2 2.8 3.3 3.2 2.5 1.4 2.5 2.2 3.4 2.6 2.901 2.901 2.1 2.2 3.7 6.1 3.2 6.6 3.5 1.6 2.5 1.4 2.5 2.2 3.4 2.2 3.4 3.3 2.8 3.9 2.8 3.96 6.56 2.0 9.16 2.0 8.36 1.4 9.16 2.0 8.86

X A, B

0.01 0.1 1 10 100 1000 10000 Time [seconds] 0.2 0.4 0.6 0.8 1 Population Density Structure A Structure B Structure X

BarMap Simulation

(no Theophylline) 0.01 0.1 1 10 100 1000 10000 Time [seconds] 0.2 0.4 0.6 0.8 1 Population Density Structure A Structure B Structure X

BarMap Simulation

(+ Theophylline)

Stefan Badelt, Stefan Hammer, Christoph Flamm, and Ivo L. Hofacker, Thermodynamic and kinetic folding of riboswitches, Methods in Enzymology, Elsevier, in press. Manja Wachsmuth, Sven Findeiß, Nadine Weissheimer, Peter F. Stadler and Mario M¨

  • rl,

De novo design of a synthetic riboswitch that regultes termination transcription, NAR, (2012) 5

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SLIDE 8

SundialsWrapper libary

  • SundialsWrapper.pm

– solving arbitrary CRNs using the Sundials CVODE C-library

RNAsubopt barriers treekin Sundials CVODE

SEQUENCE

t ✁✁✂ ✄☎✆ ✥ ✝ ✞✟ t ✥ ✄☎t
  • ✞
✥ ♠ ✠✡ ✁ ☛ ☞lar ✥ ✡✠☛ ✞✡ ✂ ✄☎ ✁tics ❈ ✌✍✎ ✏ ✆ ✥ ✟ ✡✠ ✑ ✁ ✥ ✞
  • ✒
✄t
  • ✞
  • ❛
❈ ✓ ✔ ✟ ✥ ✄☎t
  • ✞✥♠ ✠✡
✁ ☛ ☞lar ✥ ✄☎t ✁ ✥♠ ✠✡ ✁ ☛ ☞lar

Sundi

✞✡✟ ✕rapper ✳ ✖ ♠

1 100 10000 1e+06 1e+08 Time/a.u. 0.2 0.4 0.6 0.8

❇ ✞
  • ✗ ✞
✖ ✳ ✖ ♠

1 100 10000 1e+06 1e+08 Time/a.u. 0.2 0.4 0.6 0.8

6

slide-9
SLIDE 9

SundialsWrapper libary

  • SundialsWrapper.pm

– solving arbitrary CRNs using the Sundials CVODE C-library

RNAsubopt barriers treekin Sundials CVODE

SEQUENCE

✘ ✙✚✚✛ ✜✢✣ ✤ ✦ ✧★ ✘ ✤ ✜✢✘ ✙ ✧ ✤ ✩ ✪✫ ✚ ✬ ✭lar ✤ ✫✪✬ ✧✫ ✛ ✜✢ ✚tics ✮ ✯✰✱ ✲ ✣ ✤ ★ ✫✪ ✴ ✚✙ ✤ ✧ ✙ ✵ ✜✘ ✙ ✧ ✙ ✶ ✮ ✷ ✸ ★ ✤ ✜✢✘ ✙ ✧✤✩ ✪✫ ✚ ✬ ✭lar ✤ ✜✢✘ ✚✙ ✤✩ ✪✫ ✚ ✬ ✭lar

Sundi

✧✫★ ✹rapper ✺ ✻ ✩

1 100 10000 1e+06 1e+08 Time/a.u. 0.2 0.4 0.6 0.8

✼ ✧ ✙ ✽ ✧ ✻ ✺ ✻ ✩

1 100 10000 1e+06 1e+08 Time/a.u. 0.2 0.4 0.6 0.8

6

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SLIDE 10

interkin.pl kinetics of interacting molecules

  • compute intra-molecular rates for each monomer
  • compute intra-molecular rates for all interacting dimers
  • compute transition rates between monomers and dimers

barr A+B <=> AB barriers -- A,B,AB barriers -- AB

7

slide-11
SLIDE 11

RNAfolding of interacting molecules

A G A C G A U U A G U CC C A UG A C U G A U C G U C G

population density [mol/L]

1 1e+05 1e+10 arbitrary time units 0,0002 0,0004 0,0006 0,0008 0,001

A+B <=> AB

8

slide-12
SLIDE 12

RNAfolding of interacting molecules

A G A C G A U U A G U CC C A UG A C U G A U C G U C G

population density [mol/L]

1 1e+05 1e+10 arbitrary time units 0,0002 0,0004 0,0006 0,0008 0,001

A U G A C U G A U C G U C G A U G A C U G A U C G U C G

A+A <=> AA, B+B <=> BB, A+B <=> AB

8

slide-13
SLIDE 13

transkin.pl co-transcriptional folding of large RNAs

S = () for each RNAsequence of the growing chain

1 s = MFE-structure of current sequence,

unless s ∈ S { S = S + s compute refolding rates to all currently populated structures }

2 simulate CRN using SundialsWrapper

9

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SLIDE 14

transkin.pl co-transcriptional folding of large RNAs

0,01 0,1 1 10 time [s] 0,2 0,4 0,6 0,8

  • ccupancy

cotranscriptional folding (843nt)

G A A A U A U C U A A G G U A G U C U A GA G G U A G G U C C U U G U A C A G U C U C C C C GG C U C A C C U G A G C G C G G A C U A A G G G A C C U G G G C C G G A U U C U C A A G G A G G C C C A U U A G A C C U C G U C A G G G U A C G G G A C C U G C U C U C G C C U U A G G A U G G U U A C U G C C G A G G G C U A G U C C G U U G C C U A G C C U G G A A U G C C C G A U G U A A C C G A C A A C A C C A A C U U G G C U C A U G A G C U U G U A C G C G C A A A G U U U C G A U G C C C C G C G A C A C G A C A C U U A G U G C C G G U G U G U C U A G U C C G U G G A G C G G G G C U A U C U A U G A G G A A A A U A A C U U U U U U U G C G C U A A G G U A U G G A U G C U U C A G A C U A G A A A G G U A U G G A U G C U U C A G A C A U U A C A C U A U A U C A A A G U G C U G A C U G U U A A A A AU G A U C C C A A A C U A A C G G U A G A U A A A U U U A U U U G U A C A U A A C U U U AA A A G G A G U A G A A G A U U U U U U G G A A G U U U G U A A U U A C G C U A G C A A G U U U G U A A U U A C A U U C A A A G U A U A C C U U C U C U G U G C G A A A A A A G A U U U U G U U UC A C U C A U G G U U A G U C U C G C U C A C A C G G A C U G G A C A C G CG U G U A C U A G C U G U U G U G U C G C G G G G U A U C G A G A C U U U G C G U A A C C A G A U U C A U G A G C C A GC G C G G U G U U G U C G G U U G C A U C G G G U A U A G G A G C C U A G G C A A C G G A U U U G U C U U C G G U A G U G G C U G U C C U A A G G C G A A A G C A G U U C U U G U G C C C U A A C G A G G U G U AU A G G G C C U C U U U U G G A A U C C G C C C U A G G U C C C U U A G U C C G C GG A U A G G U G A G UG C C G G A G G C A G A G C A A G G A U CA A A G U G U U A C U A G C G C C C A A A G U G U U C U U U

1 9

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SLIDE 15

thanks to

This work Ivo L. Hofacker Christoph Flamm ... and the whole TBI group

Design Projects: –XOR riboswitches Peter F. Stadler Mario M¨

  • rl

Regula Arreger Gesine Domin –RNAprions Sabine M¨ uller Sonja Petkovic –co-transc. folding of 3’ UTRs Andrea Tanzer Michael T. Wolfinger Michael Jantsch Konstantin Licht Mansoureh Tajaddod

The research was funded by the Austrian Science Fund (FWF): W1207-B09, I670-B11

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