RNA Secondary Structure Prediction

Transcription

1 RNA Seondary Struture Predton BMI/CS Sprng 208 Anthony Gtter These sldes exludng thrd-party materal are lensed under CC BY-NC 4.0 by Mar Craven Coln Dewey and Anthony Gtter

2 Goals for Leture Key onepts RNA seondary struture Seondary struture features: stems loops bulges Pseudonots Nussnov algorthm Adaptng Nussnov to tae free energy nto aount 2

3 Why RNA s Interestng Messenger RNA mrna sn t the only mportant lass of RNA rbosomal RNA rrna rbosomes are omplexes that norporate several RNA subunts n addton to numerous proten unts transfer RNA trna transport amno ads to the rbosome durng translaton the spleosome whh performs ntron splng s a omplex wth several RNA unts mrornas and others that play regulatory roles many vruses e.g. HIV have RNA genomes gude RNA sequene omplementary determnes whether to leave DNA Foldng of an mrna an be nvolved n regulatng the gene s expresson 3

4 RNA Seondary Struture RNA s typally sngle stranded Foldng n large part s determned by base-parng A-U and C-G are the anonal base pars other bases wll sometmes par espeally G-U Base-pared struture s referred to as the seondary struture of RNA Related RNAs often have homologous seondary struture wthout sgnfant sequene smlarty 4

5 trna Seondary Struture Stable tertary struture 5

6 Small Subunt Rbosomal RNA Seondary Struture 6

7 6S RNA Seondary Struture 7

8 Seondary Struture Features bulge nternal loop stem harpn loop 8

9 Four Key Problems Predtng RNA seondary struture Gven: RNA sequene Do: predt seondary struture that sequene wll fold nto Fous for today Searhng for nstanes of a gven struture Gven: an RNA sequene or ts seondary struture Do: fnd sequenes that wll fold nto a smlar struture Modelng a famly of RNAs Gven: a set of RNA sequenes wth smlar seondary struture Do: onstrut a model that aptures the seondary struture regulartes of the set Identfyng novel RNA genes Gven: a par of homologous DNA sequenes Do: dentfy subsequenes that appear to have hghly onserved RNA seondary struture putatve RNA genes 9

10 RNA Foldng Assumpton Algorthms we ll onsder assume that base parngs do not ross For base-pared postons and wth < and < we must have ether < < < or < < < not nested < < < or < < < nested Can t have < < < or < < < 0

11 Pseudonots These rossngs are alled pseudonots pseudonot Dynam programmng breas down f pseudonots are allowed Fortunately they are not very frequent Modern software does support them Ayama et al. 208 Fgure from Selverstov et al. BMC Mrobology 2005

12 Smplest RNA Seondary Struture Tas Gven: Do: An RNA sequene The onstrant that pseudonots are not allowed Fnd a seondary struture for the RNA that maxmzes the number of base parng postons 2

13 Predtng RNA Seondary Struture: the Nussnov Algorthm [Nussnov et al. SIAM Journal of Appled Mathemats 978] Key dea: Do ths usng dynam programmng start wth small subsequenes progressvely wor to larger ones 3

14 DP n the Nussnov Algorthm G G G A A A U C C G G G A A A U C C max # of pared bases n subsequene [ ] Fgure 0.8 from textboo 4

15 DP n the Nussnov Algorthm Let f x and x are omplementary 0 otherwse Intalzaton: 0 for 2 to L 0 for to L Reurson - max - max max # of pared bases n subsequene [ ] 5

16 Nussnov Algorthm Traeba push L onto sta repeat untl sta s empty pop f ontnue else f push else f push else f reord base par push else for to -:f push push brea 6

17 Predtng RNA Seondary Struture by Energy Mnmzaton It s naïve to predt foldng ust by maxmzng the number of base pars However we an generalze the ey reurrene relaton so that we re mnmzng free energy nstead E E E - mnmne P E ase that and are base pared 7

18 Predtng RNA Seondary Struture by Energy Mnmzaton A sophstated program suh as Mfold [Zuer et al.] an tae nto aount free energy of the loal envronment of [ ] + mn LoopEnergy mn BulgeEnergy mn BulgeEnergy mn StangEnergy LoopEnergy mn E E l P l P P P P l 8

19 u g a u u a u g a u g - ++ u a u g a u g -l- ++ u a u g g + - g LoopEnergy BulgeEnergy mn P StangEnergy P LoopEnergy mn l P l l 9 Predtng RNA Seondary Struture by Energy Mnmzaton

20 Mfold example GGGAAAUCC ΔG = al/mol ΔG = 0.20 al/mol 20