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Improved RNA Secondary Structure Prediction by Maximizing Expected Pair AccuracyPowerPoint Presentation

Improved RNA Secondary Structure Prediction by Maximizing Expected Pair Accuracy

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### Zhi John Lu, Jason Gloor, and David H. MathewsUniversity of Rochester Medical Center, Rochester, New York

Secondary Structure Prediction by Maximizing

Expected Pair Accuracy

RNA Secondary and Tertiary Structure:

AAUUGCGGGAAAGGGGUCAA

CAGCCGUUCAGUACCAAGUC

UCAGGGGAAACUUUGAGAUG

GCCUUGCAAAGGGUAUGGUA

AUAAGCUGACGGACAUGGUC

CUAACCACGCAGCCAAGUCC

UAAGUCAACAGAUCUUCUGU

UGAUAUGGAUGCAGUUCA

Cate, et al. (Cech & Doudna).

(1996) Science 273:1678.

Waring & Davies. (1984) Gene 28: 277.

Ki =

=

= Ki/Kj =

The structure with the lowest DG° is the

most favored at a given temperature.

Nearest Neighbor Model for Free Energy Change of a Sample Hairpin Loop:

Mathews et al., J. Mol. Biol., 1999, 288: 911.

Mathews et al., PNAS, 2004, 101: 7287.

RNA Secondary Structure Prediction Accuracy: Hairpin Loop:

Percentage of Known Base Pairs Correctly Predicted:

Mathews, Disney, Childs, Schroeder, Zuker, & Turner. 2004. PNAS 101: 7287.

Limitations to Prediction of the Minimum Free Energy Structure:

- A minimum free energy structure provides the single best guess for the secondary structure.
- Assumes that:
- RNA is at equilibrium
- RNA has a single conformation
- RNA thermodynamic parameters are without error
- Non-nearest neighbor effects
- Some sequence-specific stabilities are averaged

A Method that Looks at the Probability of a Structure could be more Informative:

- A partition function can be used to determine the probability of a structure at equilibrium.

The Partition Function, Q: be more Informative:

So, what is Q good for? be more Informative:

where k is the sum over all structures with the i-j base pair.

Accuracy: be more Informative:

- Sensitivity – what percentage of known pairs occur in the predicted structure.
- Positive Predictive Value (PPV) – what percentage of predicted pairs occur in the known structure.
- PPV ≤ Sensitivity because the structures determined by comparative sequence analysis do not have all pairs and there is a tendency to over-predict base pairs by free energy minimization.

Applying P be more Informative:i,j to Structure Prediction:

PPV

PBP≥ 90%

PPV

PBP≥ 70%

PPV

PBP> 50%

Positive

Predictive

Value (PPV)

PPV

PBP≥ 99%

PPV

PBP≥ 95%

Sensitivity

Mathews. RNA. 10: 1178. (2004).

Percent of Predicted BP above Threshold: be more Informative:

PPV

PBP≥ 99%

PPV

PBP≥ 95%

PPV

PBP≥ 90%

PPV

PBP≥ 70%

PPV

PBP> 50%

Mathews. RNA. 10: 1178. (2004).

Color Annotation: be more Informative:

E. coli 5S rRNA

Structures Constructed from Highly Probable Pairs: be more Informative:

PBP≥ 99%

PBP≥ 90%

PBP≥ 70%

PBP> 50%

“Maximizing Expected Accuracy:” be more Informative:

CONTRAfold: be more Informative:

- “Statistical learning method” to predict Pi,j
- Generate structures:

Where:

Bioinformatics. 22: e90-e98. (2006).

Implement Maximum Expectation: be more Informative:

- Zhi John Lu, Jason Gloor, David Mathews
- Implement dynamic programming algorithm
using partition function prediction of Pi,j.

- Also implement suboptimal structure prediction.
- Alternative hypotheses.

Sensitivity and PPV vs. be more Informative:g:

Comparison: be more Informative:

Summary: be more Informative:

- Maximizing expected accuracy can predict structures with greater sensitivity and positive predictive value than free energy minimization.
- Maximizing expected accuracy using an underlying thermodynamic model is more accurate than an underlying statistical model.

Methanococcus thermolithotrophicus be more Informative: 5S rRNA (Szymanski et al., 1998):

MaxExpect Predicted Structure:

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