Modelling Workshop - Some Relevant Questions Prof. David Jones [e-mail] University College London

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Modelling Workshop - Some Relevant
QuestionsProf. David Jonesdtj_at_cs.ucl.ac.ukUnive
rsity College London

• Where are we now?
• Where are we going?
• Where should we be going?
• New ideas?
• Can we combine theory with experiment?
• What do users need?
• What are we trying to achieve?

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Reasons to Predict Protein Structure

• I want a picture of my protein for my thesis
• EASY but does anyone care if its wrong?
• I want to identify possible domain boundaries
• POSSIBLE
• I want to identify surface residues
• POSSIBLE
• I want some clues as to the function of my
  protein
• POSSIBLE?
• I want to dock drug molecules into the structure
• FORGET IT!

NEED TO CLEARLY DEFINE WHO WANTS THE MODELS AND
WHAT THEY WANT TO DO WITH THEM!
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How good is comparative modelling really?
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Types of Model and Production Costs

• Comparative models
• Automatic all atom model
• 1 server _at_ 200 models per day)
• 0.30/model
• Sophisticated (multi-template) automatic model
• 1 server _at_ 30 models per day)
• 2/model
• Human assisted (e.g. CASP) model
• 1 human _at_ 100 models per year)
• 200/model
• Deluxe model incorporating experimental data
• 1 human _at_ 1-4 models per year)
• 4000-50000/model
• Fold recognition models
• Automatic low resolution model
• 1 server _at_ 200 models per day
• 0.30/model
• Meta model

Assumptions Scientist salary 50000/year Server
costs (inc. maintenance support)
10000/year Beowulf costs (inc. maintenance,
support and electricity) 100000/year Costs of
experimental data not included
Archiving costs should reflect cost of generating
the models!
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Methods for Quality Control

• CASE 1 - Single PDB file with no supporting
  evidence
• This is clearly of limited use
• Can apply standard QC methods developed for X-ray
  structures (e.g. PROCHECK)
• Many incorrect models pass these checks
• Methods do exist which can generate reliability
  estimates (e.g. MODCHECK or ProQ)
• However, these methods have reliability issues of
  their own
• Can present a summary of various quality
  measures, but how can these be interpreted?
• Which quality estimators do you believe?
• CASE 2 Model submitted with supporting evidence
• Much more useful
• What evidence?
• Alignments
• Method description
• Experimental data (good but how to evaluate)
• Generating consistent quality measures based on a
  wide variety of methods and supporting evidence
  is going to require a lot of hard research
• CASE 3 Community modelling (many models for
  same target)
• Example CASP experiments or meta servers
• Can generate global and local reliability scores
  from a large population of models
• Cluster all structures using a structural
  similarity measure (which one?)