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Lecture7:RNAfolding
Chapter6–Problem6.51inJonesandPevznerandtheTurnermodel
Fall2019
September19,2019
RNABasics
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� RNAbasesA,C,G,U� CanonicalBasePairs◦ A-U◦ G-C◦ G-U“wobble”pairing◦ Basescanonlypairwithoneotherbase.
Image: http://www.bioalgorithms.info/
RNAStructuralLevels
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Primary AAUCG...CUUCUUCCA Primary
Secondary Tertiary
RNASecondaryStructure
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Hairpin loop Junction (Multiloop)
Bulge Loop
Single-Stranded
Internal Loop
Stack
Pseudoknot
BasePairMaximization
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U
C
C
A G
G
A
C
Zuker (1981) Nucleic Acids Research 9(1) 133-149
BasePairMaximization–DynamicProgrammingAlgorithm
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Simple Example: Maximizing Base Pairing
BasePairMaximization–DynamicProgrammingAlgorithm
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S(i,j) is the folding of the subsequence of the RNA strand from index i to index j which results in the highest number of base pairs
BasePairMaximization–DynamicProgrammingAlgorithm
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BasePairMaximization–DynamicProgrammingAlgorithm
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BasePairMaximization–DynamicProgrammingAlgorithm
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BasePairMaximization–DynamicProgrammingAlgorithm
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CircularRepresentation
12 Images – David Mount
Pseudoknots
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� PseudoknotscauseabreakdowninthepresentedDynamicProgrammingAlgorithm.
� Inordertoformapseudoknot,checksmustbemadetoensurebaseisnotalreadypaired–thisbreaksdownthedivideandconquerrecurrencerelations.
Images – David Mount
SimplifyingAssumptions
• RNAfoldsintooneminimumfree-energystructure.
• Therearenoknots(basepairsnevercross).• Theenergyofaparticularbasepairinadoublestrandedregionissequenceindependent.• Neighborsdonotinfluencetheenergy.
• Wassolvedbydynamicprogramming,ZuckerandSteigler1981
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SequenceDependentBasePairEnergyValues(NearestNeighborModel)
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U U C G G C A U G C A UCGAC 3’ 5’
U U C G U A A U G C A UCGAC 3’
5’
Example values: GC GC GC GC AU GC CG UA -2.3 -2.9 -3.4 -2.1
FreeEnergyComputation(NearestNeighborModel)
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U U A A G C G C A G C U A A U C G A U A 3’ A 5’
-0.3
-0.3
-1.1 mismatch of hairpin -2.9 stacking
+3.3 1nt bulge -2.9 stacking
-1.8 stacking
5’ dangling
-0.9 stacking -1.8 stacking -2.1 stacking
G= - 4.9 kcal/mol
+5.9 4 nt loop
RNASecondaryStructure
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Stack
NearestNeighborModel
• Stackingenergy-assignnegativeenergiestothesebetweenbasepairregions.• Energyisinfluencedbythenearestclosingbasepair• Theseenergiesareestimatedexperimentallyfromsmall
syntheticRNAs.
• Positiveenergy-addedforlowentropyregionssuchasbulges,loops,etc.
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RNASecondaryStructure
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Hairpin loop
NearestNeighborModel
• Hairpinenergy:• Experimentallymeasuredforhairpinsoflength5,6,7,8,…
uptoamaximum.Extrapolationabovethemaximum.
• Theclosingpairaffectstheenergy.DistinguishbetweenA-UandC-G.
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RNASecondaryStructure
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Bulge Loop
Internal Loop
NearestNeighborModel
• Bulge/Internalenergy:• LetL1,L2denotethelengthsofthetwosidesofthebulge/
internalloop.
• ExperimentallymeasuredfordifferentvaluesofL1,L2.
• Inpracticeforcomputationalconvenience,theenergyisgivenasfunctionofL1+L2byalookuptableandextrapolation.
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RNASecondaryStructure
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Junction (Multiloop)
NearestNeighborModel
• Multiloopenergy:• LetUdenotethenumberofunpairedbases.
• LetPdenotethenumberofbasepairs.• ThefreeenergyisanaffinefunctionofUandP:
a1 + a2 U + a3 P.
• ThisistheleastaccuratecomponentoftheNNmodel.
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