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Self-Organizing Bio-structures. NB2-2009 L.Duroux. Lecture 2. Macromolecular Sequences. Introduction-questions:. How do we move along from prebiotic small molecules to oligomers and polymers (DNA & proteins)? Why the need for long polymeric chains vs cooperation of small ones?

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lecture 2

Lecture 2

Macromolecular Sequences

introduction questions
Introduction-questions:
  • How do we move along from prebiotic small molecules to oligomers and polymers (DNA & proteins)?
  • Why the need for long polymeric chains vs cooperation of small ones?
    • Why are proteins long polypeptides?
slide6

A common case of ”chain-growth”:

Protein structural domains

Active site (combination of ancestral active site residues)

Chymotrypsin

Putative ancestral b-barrel structure

‘Modern’ 2-b-barrel structure

Activity 1000-10,000 times enhanced

slide8

A multiple-domain protein: pyruvate kinase

b barrel regulatory domain

a/b barrel catalytic substrate binding domain

a/b nucleotide binding domain

1 continuous + 2 discontinuous domains

co polymerization

Co-polymerization

A step towards macromolecules

model for a copolymer growth
Model for a copolymer growth

rA = kAA / kAB and rB = kBB / kBA

copolymer composition as function of r a and r b
Copolymer composition as function of rA and rB
  • Modelized by Mayo-Lewis equation
  • rA = rB >> 1 : homopolymers (AAAA or BBBB)
  • rA = rB > 1 : block-copolymer (AAAAABBBBBB)
  • rA = rB ≈ 1 : random copolymer (AABAAABBABBB)
  • rA = rB ≈ 0 : alternate copolymer (ABABABABABA)
  • Example:
    • Maleic anhydride (rA = 0.03)
    • trans-stilbene (rB = 0.03)
monomer addition by radical propagation
Monomer Addition by Radical propagation
  • The polymer chain grows by addition of monomer units:
  • radical attacks double bond of monomer
  • new radical forms that is one monomer unit longer
    • chain reaction
  • chain has propagated
  • called free radical polymerisation
radical initiation
Radical Initiation
  • Q: From where does the first unpaired electron come?
  • A: Generated by an initiator
  • e.g. hydrogen peroxide (H2O2)
    • has O–O bond (easy to break)
    • generates 2 OH• radicals
  • usually don’t use H2O2 but other peroxides, e.g.:
    • potassium persulfate
      • persulfate ion is: [O3S–O–O–SO3]2–
      • O–O bond breaks readily at 60oC to initiate reaction
some common polymers
Some Common Polymers
  • polyethylene (also called polythene)

Glad Wrap

  • polystyrene

bean bags, packing

  • poly(vinyl acetate) (PVAc)

glues, paints

  • poly(vinyl alcohol) (PVA)

glues

polypeptides polynucleotides more difficult
Polypeptides, polynucleotides: more difficult!
  • Chaincompositiondifficult to predict:
    • Severalco-monomers (20 aa, 5nt)
    • Monomer concentrationsmightvary
    • Complexinterplaybetweenmanykinetic parameters
  • Condensationpolymerization (≠ addition)
    • Thermodynamics not favorable
    • Needsactivation (energy)
formation of homo polypeptides
Formation of homo-polypeptides
  • H2O a problem !
  • Condensationpossibleonclay
  • AMP not a pre-bioticmolecule!
other routes to condensation of amino acids
Other routes to condensation of amino-acids
  • From amino-acids:
    • Possible in vesicleswithoutactivation + heat
    • Heat 180˚C + excessGlu/Aspor Lys
    • Metal ions + Drying + Heat
  • Condensation
    • HCN + addition of side chains
    • N-carboxyanhydrides (seeChap. 3)
    • Carbonylsulfide: COS (prebioticvolcanic gas)
  • Questions:
    • Whataboutchains longer than 10 amino-acids?
    • Whataboutchainsequencespecificity?
the case of polynucleotides
The case of polynucleotides
  • Activated nucleotide:
  • Phosphorimidazolide (b)
  • stereospecificity 3’-5’ (c)
  • Clay:
    • water activity reduced
    • UV-resistance
template directed oligomerization
Template-directed oligomerization

Still :

No explanation for NMPs

No explanation for the retention of particular sequences of nucleotides

aetiology of the current protein set
Aetiology of the current protein set
  • Consider a chain of 100aa : 20100 possibilities!
  • Total number of natural proteins: 1015
  • Now: 1015 / 20100 ≈ rH / runiverse
  • What about the ”never-born” or ”obliterated” proteins?
  • Only one reasonable assumption to limit the set: contingency + thermodynamics!
the never born or obliterated proteins do they fold
The ”never-born” or ”obliterated” proteins: do they fold?
  • Is there anything special about the proteins we know (energy, folding...)?
  • Experimental test:
    • Screening random-generated peptide library (50aa)
    • Do they fold?
never born proteins experimental set up
Never-Born proteins: experimental set-up

Only folded peptides resist to thrombin cleavage

80 clones tested: 20% resistant

in which conditions
In which conditions?
  • Oligopeptides formed (up to 10aa) in various libraries, in prebiotic conditions
  • Condensation of oligopeptides possible:
    • Catalytic dipeptides (seryl-histidine, histidyl-histidine)
    • Reverse reaction favoured in H2O-free medium
    • Clay support or phase-separation (product insoluble)
peptide fragments condensation
Peptide-fragments condensation

* Catalytic residue

= peptidase activity

specific to terminal

amino acid

As a result of contingency:

pH, salinity, temperature...

synthetic homochirality
Synthetic Homochirality

The case of vinyl polymers : polypropylene (G. Natta)

Confers helical conformations to polymer in crystals

theoretical model for chain chirality
Theoretical model for chain chirality
  • Enantiomeric excess:
    • (D-L)/(D+L) = 0.2
    • => 60% D + 40% L
  • Dn/Ln grows exponentially with n power (binomial distribution)
  • Enantiomeric excess = 1 when n=20!

Homo-poly-Leu

relative abundance of homochiral chains of homo polypeptides trp
Relative abundance of homochiral chains of homo-polypeptides (Trp)

White: random distribution

Grey: observed composition

Over-representation of

homochiral peptides

conclusions
Conclusions

Prebioticchemistrycouldexplain formation of short peptidechains / oligonucleotides

Still problems withactivationchemistry

CopolymerizationRulesexplainchaincomposition

Never-born proteins universe is huge: some NBP can fold

Homochirality in chains is naturallyselected, canbeexplainedstatistically.

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