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+Translational Bioinformatics
Casandra Riera
Natàlia Padilla
Òscar Marín
Elena Álvarez de la Campa
‘Amics del VHIR’
Context: where are we going? The prediction score: ◦ role ◦ components: stability, MSA
Going beyond Take home points...
What should we consider when we want to use pathogenicity predictions in a biomedical decision process
Why in some cases we can successfully interpret the pathogenicity of sequence variants, and why we fail in others
CRITICAL UNDERSTANDING OF THE PRINCIPLES UNDERLYING THE PREDICTION OF PATHOLOGICAL MUTATIONS
F367V
SC = Change in function ≈ Change in stability
MUTATION MOLECULAR IMPACT
Yue et al., J Mol Biol, 2005
Fersht, Matouschek & Serrano J Mol Biol, 1992
FoldX: Guerois et al., J Mol Biol, 2002
APPROXIMATION: (i) eliminate terms (ii) fit to in vitro exper. data
SC = SC(stability)
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Rela
tive
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ivit
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Stability (Kcal/mol)
Bromber & Rost, BMC Bioinformatics, 2009
Phage T4 Lysozyme mutants r=0.3
There is not an exact relationship between function and stability
SC(stability) is an approximation In vitro data are used to model stability in Foldx, etc
There is not an exact relationship between function and stability
SC(stability) is an approximation In vitro data are used to model stability in Foldx, etc Structure gives a qualitative view of stability change Manual analysis of 3D structures does not provide
quantitative information
SC(function) = wAcS.AcS + wCons1.Cons1 + wCons2.Cons2 + ...
Are we hitting the active site? (Yes/No)
Do we know the active site? Usually No
We can use residue conservation
How to quantify it? Use MSA and some conservation measure
APPROXIMATIONS: (i) annotations may be imprecise (ii) what conservation measure (iii) building MSAs is computationally unsolved problem (NP-hard) (iv) the weighs are empirical
SC(function) = wAcS.AcS + wCons1.Cons1 + wCons2.Cons2 + ...
Imprecise annotations (Yue et al., J Mol Biol, 2005)
MSA are suboptimal
Several conservation measures
STABILITY: ◦ There is not an exact relationship between function and stability ◦ SC(stability) is an approximation ◦ In vitro data are used to model stability in Foldx, etc ◦ Structure gives a qualitative view of stability change ◦ Manual analysis of 3D structures does not provide quantitative
information
FUNCTION: ◦ SC(function) is an approximation ◦ functional information is indirectly obtained from MSA:
prediction depends on MSA (and these are an approximation)
Protein stability Functional interactions
Unspecific cellular interactions
…KKRHCSGWL…
Y
Change in function
SC = SC(stability) + SC(function)
SC = SC(stability) + SC(function) MUTATION MOLECULAR IMPACT
PATHOLOGICAL NEUTRAL
Combine several strategies: ◦ Only use the best predictions, however,... ◦ Use several methods ◦ Manual analysis (better through
collaborations)
STABILITY: ◦ There is not an exact relationship between function and stability ◦ SC(stability) is an approximation ◦ In vitro data are used to model stability in Foldx, etc ◦ Structure gives a qualitative view of stability change ◦ Manual analysis of 3D structures does not provide quantitative
information
FUNCTION: ◦ SC(function) is an approximation ◦ functional information is indirectly obtained from MSA:
prediction depends on MSA (and these are an approximation)
GOING BEYOND: ◦ take only the best predictions ◦ use several methods ◦ look for unexpected effects