structural bioinformatics basic constraints on the structure of gene products admissible molecular...
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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
Diagnosing disease at a molecular level:
a bottom-up approach to medicine
How can we tell malfunction at the
nanoscale?
What constitutes abnormality in a “molecular
phenotype”?
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
Some background
The 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)
Microenvironment of a hydrogen bond
r
C C
HB
r
CHn (n=1,2,3)
Carbonyl O
Amide N
=15
desolvation spheres
Hydrogen-bond desolvation
across the PDB
PDB Code
C3 Q (%)
1aa2 771 52 10.18 1bz0 () 1450 95 12.03 1bz0 () 1472 99 12.00
1lou 726 47 13.05 1ris 690 45 12.87 1aue 750 49 11.80 256b 1182 75 16.05 1ubi 465 31 10.06 1gb4 240 16 10.14 1srl 120 8 15.00 12.83 2ptl 222 16 13.87 16.33 1crc 408 28 14.57 9.60 1hhh 1338 86 15.56 12.68 1mim 954 64 14.90 17.62 1ifb 645 45 14.33 8.83 1hhg 1404 95 14.77 11.09 1e4j 675 44 15.34 12.11 1e4k 699 46 15.20 11.15
1gff-1 1836 124 14.81 11.58 1csk-A 333 23 14.47 12.01
1c3t 315 21 15.00 10.78
1fas 171 23 7.43 17.08 1f94 261 25 10.44 22.80 1jwi 300 25 12.00 23.51
1dxo 645 59 10.93 21.8 1dwz 648 60 10.80 24.2 1b10 699 58 12.05 21.3 1qlx 684 58 11.79 19.6
1qm0 648 57 11.37 20.2 1qm1 639 56 11.25 21.4
Worst wrapper (survives through S-S bridges)
prions
toxins
HIV-1 protease
under-wrapped HB (dehydron)
HIV-1 protease
wrappingunder-wrapped HB (dehydron)
Complex name – PDB Code
Yint Y
10-3[Å-2]
int
10-3[Å-2]
HLA antigen A-2 + 2-microglobulin – 1i4f 6 36 1.58 3.01
Ig-light chain dimer – 1jvk 8 26 1.78 3.34
Transthyretin dimer – 1bm7 5 14 1.01 3.25
Insulin dimer - 6ins 5 22 2.80 4.51
HIV-1 protease dimer + inhibitor -1a30 7 12 1.87 4.71
SIV protease dimer - 1siv 4 14 1.06 2.65
Chey complex - 1fqw 4 10 1.02 5.07
Defensin dimer - 1dfn 8 14 2.72 10.01
Antitrypsin polyms. - 1d5s 14 22 1.01 2.76
Bombyxin - 1bon 4 5 0.60 3.02
FcRIII receptor + Ig - 1e4k, B-C 7 22 0.97 7.08
Colicin + ligand - lbxi 6 12 0.92 3.97
Colicin + ligand - 1emv 5 11 0.86 3.20
Serpin + ligand - 1as4 14 31 1.40 2.02
Troponin heterodimer - 1pon 6 10 1.34 4.54
MHC, antigen+receptor - 1im9, A-D 3 22 0.84 2.22
We have a “complete-
desolvation-shell rule”.
Are dehydrons relevant to biology or artifacts
resulting from an in vitro isolation of folding
domains?
malfunction andwrapping
hemoglobin-subunit
(5,8)
(90,94)(90,95)
Sickle-cell anemia mutation
-FG corner
Glu6-(Phe85, Leu88) interface
Quaternary 12interface
health
disease
Sickle-cell anemia
One mutation
Human prion in cellular form: the most under-wrapped of all chains in PDB
Whatever stabilizes the -kernel favors the conversion into the scrapie form.
cellular scrapie (hypothetical)
WTW T
Q217V
Mouse Doppelsame fold, but different wrapping
and…no conversion into scrapie form!
Protein-X epitope is well wrapped
(unlike in the prion)
Given our average size genome, where does our complexity come from?How is this complexity
linked to disease?
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)
myoglobinoxygen carrier in
muscleLoner
Team
SH3 domaina: caenorhabditis elegansb: homo sapiens
ubiquitinc: escherichia colid: homo sapiens
hemoglobine: paramecium (monomer)f: homo sapiens (tetramer)
= domain connectivity
scale-free interactomethrough
domain-wrappinganalysis
homo sapiens
mus musculus
escherichia coli
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.
Evolution of proteomic complexity
If the protein fold is conserved, what molecular
latitude is available to evolution?
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.
pea leghaemoglobin human haemoglobin
Sickle-cell anemia
evolution
disease
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.
2
3
4
1
Molecular basis for the evolution of proteomic complexity
Accretion 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.