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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?




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



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 fold?

Only folded peptides resist to thrombin cleavage

80 clones tested: 20% resistant



In which conditions
In which conditions? macromolecular sequences

  • 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 macromolecular sequences

* Catalytic residue

= peptidase activity

specific to terminal

amino acid

As a result of contingency:

pH, salinity, temperature...


A double independent origin of macromolecules
A double, independent origin of macromolecules? macromolecular sequences

And life could begin...?


Homochirality in chains chain growth

Homochirality in chains macromolecular sequences& chain growth


Synthetic homochirality
Synthetic Homochirality macromolecular sequences

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 macromolecular sequences

  • 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 (Trp)

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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