Structural Bioinformatics

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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

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Diagnosing disease at a molecular level a
bottom-up approach to medicine
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How can we tell malfunction at the
nanoscale?What constitutes abnormality in a
molecular phenotype?
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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
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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
Sciences USA 100, 113-118 (2003)
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Microenvironment of a hydrogen bond
CHn (n1,2,3)
Carbonyl O
r
Amide N
r
HB
Ca Ca
r15

desolvation spheres
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Hydrogen-bond desolvation across the PDB
Worst wrapper (survives through S-S bridges)
toxins
prions
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HIV-1 protease
under-wrapped HB (dehydron)
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HIV-1 protease


wrapping
under-wrapped HB (dehydron)
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We have a complete-desolvation-shell rule.
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Are dehydrons relevant to biology or artifacts
resulting from an in vitro isolation of folding
domains?
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malfunction andwrapping
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hemoglobin b-subunit
b-FG corner
(90,94) (90,95)
Sickle-cell anemia mutation
Quaternary a1b2 interface
(5,8)
Glu6-(Phe85, Leu88) interface
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Sickle-cell anemia
health
One mutation
disease
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Human prion in cellular form the most
under-wrapped of all chains in PDB
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scrapie (hypothetical)
cellular
Whatever stabilizes the b-kernel favors the
conversion into the scrapie form.
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W T
WT
Q217V
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Mouse Doppel same fold, but different
wrapping and no conversion into scrapie form!
Protein-X epitope is well wrapped (unlike in the
prion)
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Given our average size genome, where does our
complexity come from?How is this complexity
linked to disease?
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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
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SH3 domain a caenorhabditis elegans b homo
sapiens ubiquitin c escherichia coli d homo
sapiens hemoglobin e paramecium (monomer) f
homo sapiens (tetramer)
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scale-free interactome through domain-wrapping ana
lysis
mus musculus
homo sapiens
n domain connectivity
escherichia coli
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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.
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Evolution of proteomic complexityIf the protein
fold is conserved, what molecular latitude is
available to evolution?
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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.
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evolution
pea leghaemoglobin
human haemoglobin
disease
Sickle-cell anemia
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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.
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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.