Structural Bioinformatics

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Structural Bioinformatics
What is it ? What can it do for us ?
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Genomics
Sequence Data
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Genomics
Detection Monitoring of Diseases
Sequence Data

• Cancer
• Genetic abnormalities
• Alzheimers

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Genomics
Detection Monitoring of Diseases
Sequence Data

• Cancer
• Genetic abnormalities
• Alzheimers

Species comparisons
Understanding Evolution/Taxonomy
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Sequence
Expression
Structure
Interactions
Function
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What can I do with a structure?

• Deduce function
• Identify drug targets
• Compare across species

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How to determine the structure?

• X-Ray Crystallography
• NMR Spectroscopy
• Homology Modelling

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Xray Crystallography(Advantages Disadvantages)

• Detailed information
• Extremely accurate
• Works for all sizes of molecules

• Requires large amounts of very pure material
  (10-100mg)
• Obtaining crystals is more an art than science
• Can be slow and labour intensive.

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NMR Spectroscopy(Advantages Disadvantages)

• "Solution" view of the molecule.
• Dynamic information.
• Does not require any pretreatment

• Stability at high temperature (37oC) for extended
  periods.
• Requires fairly large amounts of pure material.
• Does not work for very large molecules.

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Homology Modelling

• Simple, fast.
• Does not require any physical material

• Requires accurate (experimental) structure of one
  or more homologous protein(s).
• Low accuracy unless sequence homology is
  extremely high.

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Overview of Protein Structure
H2N-C-CONH-C-CONH-C-COOH
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Overview of Protein Structure
H2N-C-CONH-C-CONH-C-COOH
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Overview of Protein Structure
H2N-C-CONH-C-CONH-C-COOH
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3D Structure Comparison

• Dejavu (Uppsala)
• DALI (EMBL)
• VAST (NIH)

Databases
CATH
SCOP
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Forces that build up a molecule
Quantum Mechanical Empirical Force
Field Knowledge Based Potentials
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Homology Modelling

• Place sequence on template structure
• Adjust sidechain positions according to rotamers
• Build loops
• Refine using PEF
• Validate using Ramachandran plots.

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Docking ligands into proteins
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Docking ligands into proteins
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Structural Bioinformatics
What does it do?
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If there is an experimental structure

• Compare structure with other known structures.
• Detailed analysis at a non-intuitive level.
• Generate hypotheses for further experimentation.

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If there is no experimental structure

• Generate a plausible model.
• Identify potential interactions.
• Identify probable Dead Ends and save the
  experimentalist some nightmares.