Chemistry and Evolution at the Origin of Life

Visions and Reality

Peter SchusterInstitut für Theoretische Chemie und Molekulare

Strukturbiologie der Universität Wien

Madrid, Astrobiology Meeting 30.11.2001

From prebiotic chemistryto the first cellularorganisms

World of c laysP rogramable c atalystsSe lf-reproducing mineralsSur face catalysis ?Reprod uction in thre e dimensions ?

Template che mistryTe mplate induced reactionsLigati on, complemen tary synthesis,molec ular copying, autocatalysisRN A precursors ?Origin of the first RN A molecules ?Ster eochemical pu rity, chirality ?Nat ure of molecu lar templates ? Non instru cted polymers

Condensation , polymerizatio n,agg regationR andom oligop eptides, proten oids,l ipid membrane s, carbohydrat es, ...Con densation ag ent ?Pol ymerization m echanism ?

E xtraterrestria l organicmolecul esHydro gen cyanide, f ormaldehyde,ami no acids, hydr oxi acids,...Mete rorites,comets , dust clouds Simulation experimentsHydrogencya nide, amino ac idshydroxiaci ds, purine base sMiller-Urey, F ischer-Tropsc h, ...Pri mordial atmo sphere ? H eating during condensation ?

?? ?? ???? ?? ?? ???? ???? ????

Sulfur b ased chemistr ySurfacecata lysis on pyrite sHydrot hermal vents

RNA WorldLigatio n, cleavage, ed iting,replication , selection, opt imization Reactions w ith nucleotide templatesR NA catalysis

Su lfur metabolis m ?Hea t gradients at deep sea volc Organi c molecules

World of clays

Programable catalysts

Self-reproducing minerals

Surface catalysis ?

Reproduction in three dimensions ?

Template chemistry

Template induced reactions

Ligation, complementary synthesis,molecular copying, autocatalysis

RNA precursors ?

Origin of the first RNA molecules ?

Stereochemical purity, chirality ?

Nature of molecular templates ?Non instructed polymers

Condensation, polymerization,aggregation

Random oligopeptides, protenoids,lipid membranes, carbohydrates, ...

Condensation agent ?

Polymerization mechanism ?

Extraterrestrial organicmolecules

Hydrogen cyanide, formaldehyde,amino acids, hydroxi acids,...

Meterorites, comets, dust clouds

Simulation experiments

Hydrogen cyanide, amino acidshydroxi acids, purine bases

Miller-Urey, Fischer-Tropsch, ...

Primordial atmosphere ? Heating during condensation?

???? ???? ???? ???? ???? ????

Sulfur based chemistry

Surface catalysis on pyritesHydrothermal vents

RNA World

Ligation, cleavage, editing,replication, selection, optimization

Reactions with nucleotide templatesRNA catalysis

Sulfur metabolism ?

Heat gradients at deep sea volcanos ?

Organic molecules

Origins of reactive organic molecules

Extraterrestrial organicmolecules

Hydrogen cyanide, formaldehyde,amino acids, hydroxi acids,...

Meterorites, comets, dust clouds

Heating during condensation?

Simulation experiments

Hydrogen cyanide, amino acidshydroxi acids, purine bases

Miller-Urey, Fischer-Tropsch, ...

Primordial atmosphere ?

Sulfur based chemistry

Surface catalysis on pyritesHydrothermal vents

Sulfur metabolism ?

Heat gradients at deep sea volcanos ?

Organic molecules

World of clays

Programable catalysts

Self-reproducing minerals

Surface catalysis ?Reproduction in three dimensions ?

Template chemistry

Template induced reactions

Ligation, complementary synthesis,molecular copying, autocatalysis

RNA precursors ?

Origin of the first RNA molecules ?

Stereochemical purity, chirality ?

Nature of molecular templates ?

Non instructed polymers

Condensation, polymerization,aggregation

Random oligopeptides, protenoids,lipid membranes, carbohydrates, ...

Condensation agent ?Polymerization mechanism ?

From small organic molecules to instructed polymers

???? ???? ???? ???? ???? ????

RNA World

Ligation, cleavage, editing,replication, selection, optimization

Reactions with nucleotide templatesRNA catalysis

From an RNA world to the first living organisms

Three-dimensional structure ofphenylalanyl-transfer-RNA

OCH2

OHO

O

PO

O

O

N1

OCH2

OHO

PO

O

O

N2

OCH2

OHO

PO

O

O

N3

OCH2

OHO

PO

O

O

N4

N A U G Ck = , , ,

3' - end

5' - end

Na

Na

Na

Na

The chemical formula of RNA consisting of nucleobases, ribose rings, phosphate groups, and sodium counterions

2

Association

Ligation

Complex dissociationAutocatalytic formation ofa hexanucleotide template from two trinucleotides

Hydrogen bonds

Hydrogen bonding between nucleotide bases is theprinciple of template action of RNA and DNA

G

G

G

G

C

C

C G

C

C

G

C

C

G

C

C

G

C

C

G

C

C

C

C

G

G

G

G

G

C

G

C

Plus Strand

Plus Strand

Minus Strand

Plus Strand

Plus Strand

Minus Strand

3'

3'

3'

3'

3'

5'

5'

5'

3'

3'

5'

5'

5'+

Complex Dissociation

Synthesis

Synthesis

Complementary replication as the simplest copying mechanism of RNA

G

G

G

C

C

C

G

C

C

G

C

C

C

G

C

C

C

G

C

G

G

G

G

C

Plus Strand

Plus Strand

Minus Strand

Plus Strand

3'

3'

3'

3'

5'

3'

5'

5'

5'

Point Mutation

Insertion

Deletion

GAA AA UCCCG

GAAUCC A CGA

GAA AAUCCCGUCCCG

GAAUCCA

Mutations represent the mechanism of variation in nucleic acids

SpaceSequence

Con

cent

ratio

n

Master Sequence

The molecular quasispecies

U

U

U

U

U

G

G

G

G

G

G G

G

G

G

G

G G

G

G

G

G

A

A

A

A

A

A

A

A

A

A

C

C

C C

C C

C

C

C

C

C C

C

C

C

Cleavage site

The "hammerhead" ribozyme

OH

OH

OH

ppp

5'

5'

3'

3'

The smallest knowncatalytically activeRNA molecules

Association

Ligation

Complex dissociation

E N T + +

E N

2 T

E

N

=

=

Ar- -CO-S-Bn

H N- -CO-NH

RMKQLEEKVYELLSKVA

CLEYEVARLKKLGE2 2

Ar- -CO-NHRMKQLEEKVYELLSKV LEYEVARLKKLVEGE 2

T

=

Ligation Site

Ar

Bn

=

=

4-Acetamidobenzoyl-

Benzyl-

Autocatalytic formation of a oligopetide template from twotwo precursor oligopeptides

L5

L5

R1

R1

M2

M2

K3

K3

Q4

Q4

E7E7

E6

E6

LEKK

29

22

15

8

KKEL

8

15

22

29

LLL

12

19

26

VVVV

9

16

23

30LEK

13

20

27

ECRE

11

18

25

32

Y10

A24G31

SYK

14

21

28

ER

E

32

25

11

KEL

27

20

13V30V23V16V9

GAAY

31

24

17

10

SYK

14

21

28

LLL

26

19

12

Color code for amino acid residues

hydrophobic

hydrophilic, neutral

positively charged

indifferent

negatively charged

The a-helix wheel illustrating template action of oligopeptides by means of hydrophobic interaction

The three-dimensional structure of a short B-DNA double helix

Three-dimensional structure of thecomplex between the regulatoryprotein cro-repressor and the bindingsite on l-phage B-DNA

++

Replication:DNA 2 DNA→

Tran

scrip

tion:

DN

A

RN

A→

Metabolism

Food

Waste

Nucleotides

Amino Acids

Lipids

Carbohydrates

Small Molecules

Translation: RNA Protein→

ProteinmRNA

Ribosom

Information processing and metabolism in the DNA-RNA-protein world

Stock Solution Reaction Mixture

The flowreactor as a device for studies of evolution in vitro and in silico

0 250 500 750 1000 1250

Time

0

10

20

30

40

50A

vera

ge d

ista

nce

of th

e po

pula

tion

from

targ

etMajor changes in phenotypes

Num

ber

of p

heno

type

s in

the

rela

y se

ries

Evolution in silico in the flow reactor

Genotype Space

Fitn

ess

Start of Walk

End of Walk

Random Drift Periods

Adaptive Periods

Evolution in genotype space sketched as a non-descending walk in a fitness landscape

yes

Selection Cycle

no

GeneticDiversity

Desired Properties? ? ?

Selection

Amplification

Diversification

Selection cycle used inapplied molecular evolutionto design molecules withpredefined properties

Retention of binders Elution of binders

Chr

omat

ogra

phic

col

umn

The SELEX technique for the evolutionary design of aptamers

Stage I:Independent CompetingReplicators

Stage II:Functionally CoupledReplicators

Stage III:

New Unit of Selection

Stage IV = I:Independent CompetingUnits

Parasite

Parasite

The hypercycle model of major evolutionary transitions

Coworkers

Walter Fontana, Santa Fe Institute, NM

Christian Reidys, Christian Forst, Los Alamos National Laboratory, NM

Peter Stadler, Universität Wien, AT,Ivo L.Hofacker

Christoph Flamm

Bärbel Stadler, Andreas Wernitznig, Universität Wien, AT,Stefanie Widder, Ulrike Mückstein, Stefan Wuchty

Ulrike Göbel, Institut für Molekulare Biotechnologie, Jena, GE,Walter Grüner, Stefan Kopp, Jaqueline Weber