Self-replicating Molecules: An introduction

TSRI Chemistry Journal Club 5/11/07 Brian Frezza

Self-ReplicationA Brief Introduction To Self-propagating

Chemical Information

Why Study Chemical Self-Replication

• Evolution– One of the requirements for an evolvable

system

• Amplification– Inherent amplification useful for Chemical and

Biological sensors.

• Computation– Differential self-replication

• “The Stuff of Life”

A Broader Definition of Self-Replication

• Traditionally Definition– Joining Reaction

• Consider a broader non-classical definition– Any Chemical Information Capable of Reproducing itself.

– What is Chemical Information?• Empirical Uniqueness

– Covalent Structure– Supra-Molecular Interactions– Conformation– Etc…

T•TA + B

T

BA

B

Talk Outline• Ligation Based Systems

– Bio-organic• Hexadeoxynucleotide• RNA Ligase• Peptides

– Synthetic• 3 Small Molecule Systems

• Cleavage Based Systems– Ribozymes

• Compartmentalization Based Systems– Autopoiesis (Self-replication of Compartments)

• Micelles and Reverse Micelles– Self-replication of Location

• Encapsulated Reagents

• Conformation Based Systems– Hybridization Chain Reaction– Prions and Amyloids

*unpublished work

Ligation Based Self-Replication

ɛ = k*/kBg

kBg

Ligation Based Self-Replication• Requirements:

1. Template substrate complex A•B•T forms readily2. Template substantially accelerates the rate of it’s own production

– Symmetry requires a palindromic template3. Release of newly formed template occurs readily

• Experimental Parameters– Epsilon (ɛ)

• Autocatalytic Efficiency (ɛ = k*/kBg )• Ratio of template-catalyzed rate over the template independent rate

– ɛ < 1, background reaction faster then template reaction – ɛ approaches ∞, no background reaction

– Order (P)• Order of reaction

– P=0.5» Rate-limiting dissociation» Parabolic amplification» Rate proportional to the square root of initial template concentration

1. P=1.01. Efficient dissociation2. Exponential amplification3. Rate linearly proportional to the initial template concentration

Hexadeoxynucleotide Self-Replication

Kiedrowski, G. Angew. Chem. Int. Ed. 1986, 25, 932-935.




0 mM Template

0.2 mM Template0.4 mM Template0.8 mM Template

P = 0.48

ɛ = ~25


RNA Ligase Self-Replication

Paul, N.; Joyce, G. F. Proc. Natl. Acad. Sci. U. S. A. 2002, 99, 12733-40.




P = ~1

ɛ = 3.0*108


Peptide Self-Replication

Lee, D. H.; Granja, J. R.; Martinez, J. A.; Severin, K.; Ghadri, M. R. Nature 1996, 382, 525-8.





0 uM Template

5 uM Template10 uM Template

20 uM Template

40 uM Template

P = ~0.5

ɛ = ~500


• Modifications:– Shorter Template

• Issac, R.; Chmielewski, J. J. Am. Chem. Soc. 2002, 124, 6808-9.

– P=0.91– ɛ=1.0*105

– Proline “kink” substitution• Li, X.; Chmielewski, J. J. Am. Chem. Soc. 2003, 125, 11820-1.

– P=0.91– ɛ=3.2*104

Small Molecule Self-Replication

Tjivikua, T.; Ballester, P.; Rebek, J. J. Am. Chem. Soc. 1990, 112, 1249-1250.Wintner, E. A.; Conn, M. M.; Rebek, J. J. Am. Chem. Soc. 1994, 116, 8877-8884.


Tjivikua, T.; Ballester, P.; Rebek, J. J. Am. Chem. Soc. 1990, 112, 1249-1250.

A + B T A•B•T T•T

Wintner, E. A.; Conn, M. M.; Rebek, J. J. Am. Chem. Soc. 1994, 116, 8877-8884.

+


P = ~0.5

ɛ = ~22

A + B T

Tjivikua, T.; Ballester, P.; Rebek, J. J. Am. Chem. Soc. 1990, 112, 1249-1250.Wintner, E. A.; Conn, M. M.; Rebek, J. J. Am. Chem. Soc. 1994, 116, 8877-8884.


Terfort, A.; Kiedrowski, G. Angew. Chem. Int. Ed. 1992, 31, 654-656.





0 Equiv. Template

0.1 Equiv. Template

0.2 Equiv. Template

0.4 Equiv. Template

P = ~0.5

ɛ = ~16.4


Pearson, R. J.; Kassianidis, E.; Slawin, A. M.; Philp, D. Org. Biomol. Chem. 2004, 2, 3434-41.

Kassianidis, E.; Philp, D. Chem. Commun. 2006, 4072-4.Kassianidis, E.; Philp, D. Angew. Chem. Int. Ed. 2006, 45, 6344-6348.

Pearson, R. J.; Kassianidis, E.; Slawin, A. M.; Philp, D. Chen. Eur. J. 2006, 12, 6829-40.



A + BT



+





P = ~0.1

ɛ = ~8

Cleavage Based Self-Replication

A + AA•A

A

• Rather then bond making, active self-replicators are triggered by bond breaking

– No Product Inhibition (P = 1)

Cross-Catalytic Ribozymes

Levy, M.; Ellington, A. D. Proc. Natl. Acad. Sci. U. S. A. 2003, 100, 6416-6421.

Cross-Catalytic Ribozymes

Levy, M.; Ellington, A. D. Proc. Natl. Acad. Sci. U. S. A. 2003, 100, 6416-6421.

P = 1

ɛ = 1.2*109

Autopoiesis• A Compartment that catalyses the

construction of more compartments.

Reverse Micelles

Bachmann, P. A.; Walde, P.; Luisi, P. L.; Lang, J. J. Am. Chem. Soc. 1990, 112, 8200-8201.Bachmann, P. A.; Walde, P.; Luisi, P. L.; Lang, J. J. Am. Chem. Soc. 1991, 113, 8204-8209.

Bachmann, P. A.; Luisi, P. L.; Lang, J. Nature 1992, 357, 57-59.

Reverse Micelles



Reverse Micelles



Locational Self-Replication

• Free Molecule X Can Catalyze the release of molecule X from Compartment A

XX

XXXX

XX

XX

X

X + X

Encapsulated Reagents

Chen, J.; Korner, S.; Craig, S. L.; Lin, S.; Rudkevich, D. M.; Rebek, J., Jr. Proc. Natl. Acad. Sci. U. S. A. 2002, 99, 2593-6.

Encapsulated Reagents

Chen, J.; Korner, S.; Craig, S. L.; Lin, S.; Rudkevich, D. M.; Rebek, J., Jr. Proc. Natl. Acad. Sci. U. S. A. 2002, 99, 2593-6.

Conformation Based Self-Replication

• Molecule A has multiple conformations, A* is a self-replicating conformation which templates conformational change of A into A*

A*•A*A

A*

Hybridization Chain Reaction (HCR)

B’A’

+

B’

BA’

C’

+B’

BC

A

Dirks, R. M.; Pierce, N. A. Proc. Natl. Acad. Sci. U. S. A. 2004, 101, 15275-8.

Prions and Amyloids

• A suspected mode of action of a Prion disease is conformational self-replication that allows aggregates of the replicating conformation of a protein to accumulate in long beta sheet’s called Amyloids.

AA*

(A*• A*•)n

Conclusions

• Examples of Classic Self-Replicating by ligation have been demonstrated.– Improved catalytic efficiencies and reaction

orders have been achieved. – More examples and expanded applications of

self-replicators are of great interest.

• We have just begun to explore Non-classical forms of “Self-Replication”– New examples, new forms, and new

applications leave many exciting possibilities!

Education

Self-replicating Molecules: An introduction