Finding the building blocks of RNA 3-D structure using graph analysis

Finding the building blocks of RNA 3-D structure using graph analysisRomain RivireAReNa 28.03.2007Interest in RNA modellingCharacterise RNA families

Improve non-coding RNA identification in genomic data

Determine the RNA players in regulatory networks

Identify potential RNA drug targets

ProjectBackground: ribonomics is curently stuck with the secondary structure paradigm, whereas we would need high throughput tertiary data

Hypothesis: Finding the fundamental building blocks of RNA structures will reduce the complexity of RNA foldingRNA 3-D Structure interactions

From 3-D Structure to Graph :MC-Annotate

Yeast tRNA-Phe crystal structure(pdb 4TNA)Solution in 3 stepsEnumerate all the motifs

Regroup by similarity

Find the building blocksEnumerating motifs : The backbone helps !

Enumerating motifs

A motif is a set of connected nucleotides together with their interactionsEnumerating motifs

344 motifs of size 4 in tRNA

Solution in 3 stepsEnumerate all the motifs

Regroup by similarity

Find the building blocksGraph Isomorphism125430 1 0 0 11 0 1 1 00 1 0 1 00 1 1 0 11 0 0 1 0125430 1 0 1 11 0 1 1 00 1 0 0 11 1 0 0 01 0 1 0 0241350 1 0 0 11 0 1 1 00 1 0 1 00 1 1 0 11 0 0 1 0Matrix representation of the graph :21==Scan through all permutations to decide

if two graphs are isomorphic !Group motifs with isomorphism????????13Canonical labelling125430 1 0 0 11 0 1 1 00 1 0 1 00 1 1 0 11 0 0 1 0125430 1 0 1 11 0 1 1 00 1 0 0 11 1 0 0 01 0 1 0 0241350 1 0 0 11 0 1 1 00 1 0 1 00 1 1 0 11 0 0 1 0Matrix representation of the graph :21==Take the minimum through all permutations of the matrix representationGroup motifs with canonical labelling18211833212115Solution in 3 stepsEnumerate all the motifs

Regroup by similarity

Find the building blocksOccurrences of a motif in the 50S rRNA of H. marismortui

The covering graph : a mapping between motifs and edges

Type of motifsEdges

77710564430Find a small set of types of motifs that covers the most edgesBuilding blocks of the 50S?(graphs of size 4)

General graphs are not compact enough

Not usable for modelling

334 Building blocks of the 50S(cycles of sizes 3 to 6)

The colored Ribosome

The colored 16S

Covering for the PDB database

Future worksMotif discoveryBiological relevance of block-function relationships?

RNA foldingPractical usability? AcknowledgmentsFranois MajorSbastien LemieuxVronique LisiKarine St-OngePhilippe ThibaultPatrick GendronMartin LaroseAll other lab members

Thank youThe ResultsWe applied the method to the large ribosomal subunit

We restrict the graphs allowed for the base to cycles

We found 334 cycles that covers 90% of the structure.Canonical labelingCanonical label of a graph : Take the minimum of the matrices over all the permutations

Property : 2 graphs have the same canonical label if and only if they are isomorphicSecond step : group motifsGroup together motifs which are identicalDone with canonical labellingIdea : associate a string to each graph such that two graphs are associated with the same string if and only if they are identical (isomorphic).Difficult problem well studiedPotentially highly computation time.The construction of a bipartite graph

Conformational space too large3^n . 10^n where n is the size of the structure

10^14 op/s world fastest computerLetter A : GC base paire

Letter Sarcin Riccin

Letter GNRA

Letter crossing

Letter GNRA (2)

Interests in RNARNA is a very important medium in the transfer of genetic information

Convey information through its structure in addition to its sequence

Example : miRNAmiRNA Pathway

Structure of an miRNA

Similar secondary structure

But, only one miRNA functional !RNA 3-D Structure ineractions3 main types of molecular interactions :Phosphodiester linkBase pairingBase stackingRNA 3-D Structure interactions : Backbone connectivity

RNA 3-D Structure interactions : Base pairing types

RNA 3-D Structure interations : Base stacking types