Secondary structure prediction of RNA complexes Audrey Legendre , - PowerPoint PPT Presentation

Colloque MASIM@Journées BIM 2019 Secondary structure prediction of RNA complexes Audrey Legendre , Eric Angel, Fariza Tahi 05/11/2019 Audrey Legendre , Eric Angel, Fariza Tahi 05/11/2019 1 / 21

CONTEXT Audrey Legendre , Eric Angel, Fariza Tahi 05/11/2019 2 / 21

RNA structures and interactions Primary structure Secondary structure Tertiary structure GCGGAUUUAGCUCAGUU GGGAGAGCGCCAGACUG AAGAPCUGGAGGUCCUG UGUPCGAUCCACAGAAU UCGCACCA (PDB) RNA stability RNA-RNA interaction Riboswitch (Seeliger et al., 2012) → RNA complexes Audrey Legendre , Eric Angel, Fariza Tahi 05/11/2019 3 / 21

RNA structures and interactions Primary structure Secondary structure Tertiary structure GCGGAUUUAGCUCAGUU GGGAGAGCGCCAGACUG AAGAPCUGGAGGUCCUG UGUPCGAUCCACAGAAU UCGCACCA (PDB) RNA stability RNA-RNA interaction Riboswitch (Seeliger et al., 2012) → Need to predict several structures → RNA complexes Audrey Legendre , Eric Angel, Fariza Tahi 05/11/2019 3 / 21

RNA structures and interactions Primary structure Secondary structure Tertiary structure GCGGAUUUAGCUCAGUU GGGAGAGCGCCAGACUG AAGAPCUGGAGGUCCUG UGUPCGAUCCACAGAAU UCGCACCA (PDB) RNA stability RNA-RNA interaction Riboswitch (Seeliger et al., 2012) → Need to predict several structures → RNA complexes Audrey Legendre , Eric Angel, Fariza Tahi 05/11/2019 3 / 21

Motifs of RNA structures and interactions Internal pseudoknot Single RNA representation External pseudoknot Motif-free interaction Audrey Legendre , Eric Angel, Fariza Tahi 05/11/2019 4 / 21

Pseudoknot motifs Pseudoknot types (Taufer et al., 2008) Pseudoknot depth Pseudoknot of depth 3 Decomposition into 3 subsets without pseudoknot: Audrey Legendre , Eric Angel, Fariza Tahi 05/11/2019 5 / 21

Experimental data on RNA structure • Structural data: SHAPE, DMS, PARS • User knowledge: base pair, single base, motifs, . . . (Deigan et al., 2009) Audrey Legendre , Eric Angel, Fariza Tahi 05/11/2019 6 / 21

Our goal Predict RNA complex secondary structure • with different motifs (pseudoknots), • taking into account experimental data, • and returning several solutions. State-of-art Tools Pseudoknots Several Experimental solutions data NanoFolder (Bindewald � ✗ ✗ et al., 2016) tr NUPACK tr (Zadeh ✗ � ✗ et al., 2011) MultiRNAFold ✗ ✗ ✗ (Andronescu et al., 2005) Audrey Legendre , Eric Angel, Fariza Tahi 05/11/2019 7 / 21

METHODS RCPred C-RCPred ( RNA Complex Prediction ) ( Constrained RNA Complex Prediction ) Audrey Legendre , Eric Angel, Fariza Tahi 05/11/2019 8 / 21

Principle of our methods RNA sequences RNA-RNA interactions RNA secondary structures RNAsubopt (Lorenz et al., 2011) BiokoP (Legendre et al., 2018) pKiss (Janssen and Giegerich, 2014) RNAsubopt (Lorenz et al., 2011) RCPred Mono-objective: truc truc MFE truc RNA complexes Visualisation Audrey Legendre , Eric Angel, Fariza Tahi 05/11/2019 9 / 21

Principle of our methods RNA sequences RNA-RNA interactions RNA secondary structures RNAsubopt (Lorenz et al., 2011) BiokoP (Legendre et al., 2018) pKiss (Janssen and Giegerich, 2014) RNAsubopt (Lorenz et al., 2011) C-RCPred Multi-objective: User constraints truc Structural data User constraints truc MFE truc Structural data RNA complexes Visualisation Audrey Legendre , Eric Angel, Fariza Tahi 05/11/2019 9 / 21

Principle of our methods RNA sequences RNA-RNA interactions RNA secondary structures RNAsubopt (Lorenz et al., 2011) BiokoP (Legendre et al., 2018) pKiss (Janssen and Giegerich, 2014) RNAsubopt (Lorenz et al., 2011) C-RCPred Multi-objective: User constraints truc Structural data User constraints truc MFE truc Structural data Clustering Interactivity RNA complexes Visualisation Audrey Legendre , Eric Angel, Fariza Tahi 05/11/2019 9 / 21

Algorithmic approach Finding RNA complexes RCPred • RNA complex: set of secondary structures and interactions all -3.1 compatible between each other -1.6 s2 → Finding a clique in a graph -5.6 s3 -14.8 s1 i1 Undirected weighted graph i2 -4.5 • s vertices: secondary structures i3 i4 -5.6 • i vertices: interactions -3.5 -4.7 i5 • Edges: the two linked vertices are -6.1 compatible truc Mono-objective: truc Free energy User constraints truc Structural data Audrey Legendre , Eric Angel, Fariza Tahi 05/11/2019 10 / 21

Algorithmic approach Finding RNA complexes RCPred • RNA complex: set of secondary structures and interactions all -3.1 compatible between each other -1.6 s2 → Finding a clique in a graph -5.6 s3 -14.8 s1 i1 Undirected weighted graph i2 -4.5 • s vertices: secondary structures i3 i4 -5.6 -3.5 -4.7 • i vertices: interactions i5 • Edges: the two linked vertices are -6.1 compatible Structure 1 / Structure 2 Mono-objective: Free energy User constraints • Structural data Audrey Legendre , Eric Angel, Fariza Tahi 05/11/2019 10 / 21

Algorithmic approach Finding RNA complexes RCPred • RNA complex: set of secondary structures and interactions all -3.1 compatible between each other -1.6 s2 → Finding a clique in a graph -5.6 s3 -14.8 s1 i1 Undirected weighted graph i2 -4.5 • s vertices: secondary structures i3 i4 -5.6 • i vertices: interactions -3.5 -4.7 i5 • Edges: the two linked vertices are -6.1 compatible truc Mono-objective: truc Free energy User constraints truc Structural data Audrey Legendre , Eric Angel, Fariza Tahi 05/11/2019 10 / 21

Algorithmic approach Finding RNA complexes C-RCPred • RNA complex: set of secondary -3.1 structures and interactions all 80 -1.6 0.75 compatible between each other 75 -5.6 0.7 60 s2 → Finding a clique in a graph 0.65 s3 -14.8 235 s1 2.95 i1 Undirected weighted graph i2 -4.5 • s vertices: secondary structures i3 80 i4 -5.6 0.9 0 • i vertices: interactions -3.5 -4.7 0.8 0.5 i5 60 • Edges: the two linked vertices are 0.75 0.6 -6.1 70 compatible 0.7 truc Multi-objective: truc Free energy User constraints truc Structural data Audrey Legendre , Eric Angel, Fariza Tahi 05/11/2019 10 / 21

Algorithmic approach Clique problem: NP-hard → use of approximate algorithm (Wu and Hao, 2015) -3.1 Heuristic Breakout local search (Benlic and -1.6 s2 Hao, 2013) -5.6 s3 • Modify the solution at each iteration. s1 i1 • Movement : adding, remove or replace i2 -4.5 a vertex, reinitialize the clique. i3 i4 -5.6 -3.5 -4.7 • Choose the best movement among the i5 neighborhood. -6.1 Audrey Legendre , Eric Angel, Fariza Tahi 05/11/2019 11 / 21

Algorithmic approach Adaptation of the Breakout local search heuristic • RCPred • • • • • • • • • save sub-optimal solutions. • C-RCPred : • Generate and save the Pareto set for three objectives, • Modification of the choice of the movements, • Control of the pseudoknot depth. Audrey Legendre , Eric Angel, Fariza Tahi 05/11/2019 12 / 21

RESULTS Audrey Legendre , Eric Angel, Fariza Tahi 05/11/2019 13 / 21

RCPred results Data and protocol RNA sequences of 90 RNA complexes from RNA STRAND (Andronescu et al., 2008) RNA secondary structures RNA-RNA interactions 30 solutions of BiokoP (Legendre et al., 2018) 30 solutions of RNAsubopt 30 solutions of pKiss (Janssen and Giegerich, 2014) (Lorenz et al., 2011) 30 solutions of RNAsubopt (Lorenz et al., 2011) RCPred 10 first RNA complexes Audrey Legendre , Eric Angel, Fariza Tahi 05/11/2019 14 / 21

RCPred results Importance of returning sub-optimal solutions → The best solution is not always the MFE structure. Audrey Legendre , Eric Angel, Fariza Tahi 05/11/2019 15 / 21

RCPred results Comparison to the state-of-art RCPred* NUPACK* (Zadeh et al., 2011) NanoFolder** (Bindewald et al., 2016) MultiRNAFold** (Andronescu et al., 2005) * RCPred, NUPACK: best among 10 first solutions ** one solution is returned → RCPred performs better than the tools of the literature. Audrey Legendre , Eric Angel, Fariza Tahi 05/11/2019 16 / 21

C-RCPred results Data and protocol for evaluation of structural data criteria RNA sequences of square complex (Dibrov et al., 2011) RNA secondary structures RNA-RNA interactions 30 solutions of BiokoP (Legendre et al., 2018) 30 solutions of RNAsubopt 30 solutions of pKiss (Janssen and Giegerich, 2014) (Lorenz et al., 2011) 30 solutions of RNAsubopt (Lorenz et al., 2011) Structural data SHAPE data C-RCPred (Mauger et al., 2015) 10 first RNA complexes Audrey Legendre , Eric Angel, Fariza Tahi 05/11/2019 17 / 21

C-RCPred results Evaluation on square complex → Poor performance Audrey Legendre , Eric Angel, Fariza Tahi 05/11/2019 18 / 21

C-RCPred results Evaluation on square complex → Poor performance Observation → Low quality of pre- dicted secondary struc- tures and interactions Audrey Legendre , Eric Angel, Fariza Tahi 05/11/2019 18 / 21

C-RCPred results Data and protocol for evaluation of user constraint criteria RNA sequences of PDB_01165 complex from RNA STRAND (Andronescu et al., 2008) RNA secondary structures RNA-RNA interactions 30 solutions of BiokoP (Legendre et al., 2018) 30 solutions of RNAsubopt 30 solutions of pKiss (Janssen and Giegerich, 2014) (Lorenz et al., 2011) 30 solutions of RNAsubopt (Lorenz et al., 2011) C-RCPred User constraints 10 first RNA complexes Audrey Legendre , Eric Angel, Fariza Tahi 05/11/2019 19 / 21