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Structural Bioinformatics

Structural Bioinformatics. Basic constraints on the structure of gene products Admissible molecular phenotypes Disease and molecular malfunction Emergence of disease tied up to evolution of complexity. Diagnosing disease at a molecular level: a bottom-up approach to medicine.

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Structural Bioinformatics

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  1. Structural Bioinformatics • Basic constraints on the structure of gene products • Admissible molecular phenotypes • Disease and molecular malfunction • Emergence of disease tied up to evolution of complexity

  2. Diagnosing disease at a molecular level: a bottom-up approach to medicine

  3. How can we tell malfunction at the nanoscale?What constitutes abnormality in a “molecular phenotype”?

  4. Water is nurturing, it sustains life, but it also imposes severe constraints on what life may be like.These constraints become apparent at the molecular level but have been largely overlooked.Imbalance  disease

  5. Some backgroundThe protein molecule contains polar and nonpolar groups. The polar groups interact in very specific ways as the chain collapses. These interactions only prevail in water if they are properly “wrapped” by the nonpolar groups.A. Fernández and H. A. Scheraga, Proceedings of the National Academy of SciencesUSA100, 113-118 (2003)

  6. Microenvironment of a hydrogen bond CHn (n=1,2,3) Carbonyl O r Amide N r HB CaCa r=15 desolvation spheres

  7. Hydrogen-bond desolvation across the PDB Worst wrapper (survives through S-S bridges) toxins prions

  8. HIV-1 protease under-wrapped HB (dehydron)

  9. HIV-1 protease wrapping under-wrapped HB (dehydron)

  10. We have a “complete-desolvation-shell rule”.

  11. Are dehydrons relevant to biology or artifacts resulting from an in vitro isolation of folding domains?

  12. malfunction andwrapping

  13. hemoglobin b-subunit b-FG corner (90,94) (90,95) Sickle-cell anemia mutation Quaternary a1b2 interface (5,8) Glu6-(Phe85, Leu88) interface

  14. Sickle-cell anemia health One mutation disease

  15. Human prion in cellular form: the most under-wrapped of all chains in PDB

  16. scrapie (hypothetical) cellular Whatever stabilizes the b-kernel favors the conversion into the scrapie form.

  17. W T WT Q217V

  18. Mouse Doppel same fold, but different wrapping and… no conversion into scrapie form! Protein-X epitope is well wrapped (unlike in the prion)

  19. Given our average size genome, where does our complexity come from?How is this complexity linked to disease?

  20. myoglobin oxygen carrier in muscle Loner Being more under-wrapped, our proteins are more interactive. Their structural integrity requires binding partners. (But then there are more chances something might go wrong) Team

  21. SH3 domain a: caenorhabditis elegans b: homo sapiens ubiquitin c: escherichia coli d: homo sapiens hemoglobin e: paramecium (monomer) f: homo sapiens (tetramer)

  22. scale-free interactome through domain-wrapping analysis mus musculus homo sapiens n = domain connectivity escherichia coli

  23. Disease: a prize we pay for our complexity.A rational approach to therapy requires understanding complexity at its most basic level. Wrapping might be a key concept, since it reveals deficiencies in the relation with the solvent environment.

  24. Evolution of proteomic complexityIf the protein fold is conserved, what molecular latitude is available to evolution?

  25. A: minor alteration of wrapping; B: structure susceptibility is altered; C: dehydrons conserved, new dehydrons formed concurrently with gene duplication; D: dehydrons are not conserved; E: structural integrity compromised.

  26. evolution pea leghaemoglobin human haemoglobin disease Sickle-cell anemia

  27. 4 3 2 1 Extent of wrapping of yeast domain folds versus the ancestry of the proteins. r-value dispersions in an ancestry group are shown as error bars. Selected families are plotted. Listed in decreasing dehydron density, they are: group 4: P-loop NTP hydrolases (signal transduction), ARM repeat; group 3: protein kinases (PK), phospholipase C/P1 nucleases, class II aaRS biotin synthetases; group 2: Rossman fold domains, NAD(P) binding, trypsin-like serine proteases, EF-hand; group 1: nucleotydyl transferases.

  28. Molecular basis for the evolution of proteomic complexityAccretion of protein connections is autocatalytic, since the rate of formation of dehydrons is proportional to the number of pre-existing dehydrons. The latter, in turn, define the susceptibility of the structure to mutation.

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