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Bioinformatics – The Premier Biological
Research Tool?Warren Kaplan
Peter Wills Bioinformatics Centre
Garvan Institute of Medical Research
“One of the major goals of Bioinformatics is to understand the relationship between amino acid sequence and three-dimensional structure in proteins. If this relationship were known, then the structure of a protein could be reliably predicted from the amino acid sequence.”
David W. Mount
Current Status for Protein Structures
23382 Experimentally solved structures in the PDB
~7000 Unique Structures from NRPDB
Mainly soluble easily crystalized proteins
But if protein structures contain so much information how can this be?
225 Structures of Unknown Function
How would we typically go about assigning function to
a structure?
Experimental Validation e.g. functional assays
Bioinformatics• BLAST• VAST/CE
While these tools have failed for these 225 structures,
historically we have been very successful in seeing what originally was not clearly
evident
Is ditchwater dull? Naturalists with microscopes have told me that it
teems with quiet fun. G. K. CHESTERTON, The Spice of Life , 1936
Glycine Receptor
Absalom, N. L., T. M. Lewis, Kaplan, W., Pierce, K.D., & Schofield, P.R. (2003). "Role of charged residues in coupling ligand binding and channel activation in the extracellular domain of the glycine receptor." J Biol Chem
siRNA
gi|942577|gb|U22445.1|MMU22445 Mus musculus serine/threonine kinase (Akt2) mRNA, complete cdsFor triplet filtering there were 34 matches, 0 were removed, there are now 34 matchesFor percentage filtering there were 34 matches, 31 were removed, there are now 3 matches331 AAGGAGAGGCCCGAGGCCCC 351 75.0 __**_*_******_****** 80.01384 AAGCAGAGGCTCGGCGGAGG 1404 70.0 __**_*_***_******_** 80.0547 AAGCAGCGGGGCCCAGGTGA 567 70.0 __**_*********_**_*_ 90.0
PyView
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Lai, P., W. Kaplan, Church, W.B., & Wong, R.K. (2004). Informative 3D Visualization of Multiple Protein Structures. The Second Asia-Pacific Bioinformatics Conference (APBC2004), Dunedin, New Zealand, Conferences in Research and Practice in Information Technology - Conf.Res.Prac.Inf.Tech
Fundamentally a very easy problem to define
Maybe we aren’t spending enough time understanding what the real problems are
Can we be relying only on the biologists to write specifications?
Why are there examples where someone who has spent 6 months learning about microarrays only then realises that the data is representative of a gene and an associated level of expression?
Specifications can’t be written in a day - but being close enough to the problem can eliminate the need for extensive specs
Great software in the past was written by an individual or a few individuals:
Steven Wolfram wrote Mathematica in a summer
Ken Thompson wrote UNIX
We have to be true experts in the tools we use and develop, but we need to terribly intimate with the biology that we’re hoping to contribute to.
This is the great challenge