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.