Self-replicating Molecules: An introduction
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The document discusses various methods of chemical self-replication, including ligation-based systems using hexadeoxynucleotides, RNA ligase, and peptides that have demonstrated exponential or near-exponential amplification. It also describes cleavage-based self-replication by ribozymes, compartmentalization-based systems using reverse micelles and encapsulated reagents, and conformation-based systems like hybridization chain reactions and prion-like protein aggregation. The document concludes that while examples of classic template-directed ligation self-replication have been achieved, more work is still needed to improve catalytic efficiencies and explore new forms and applications of chemical self-replication.
Self-replicating Molecules: An introduction
- 1. Self-Replication A Brief Introduction To Self-propagating Chemical Information TSRI Chemistry Journal Club 5/11/07 Brian Frezza
- 2. 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”
- 3. 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 •T A + B T B A B
- 4. 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of Location Encapsulated Reagents Conformation Based Systems Hybridization Chain Reaction Prions and Amyloids *unpublished work
- 5. Ligation Based Self-Replication ɛ = k*/k Bg k Bg
- 6. Ligation Based Self-Replication Requirements: Template substrate complex A • B • T forms readily Template substantially accelerates the rate of it’s own production Symmetry requires a palindromic template Release of newly formed template occurs readily Experimental Parameters Epsilon (ɛ) Autocatalytic Efficiency (ɛ = k */ k Bg ) 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 P=1.0 Efficient dissociation Exponential amplification Rate linearly proportional to the initial template concentration
- 7. Hexadeoxynucleotide Self-Replication Kiedrowski, G. Angew. Chem. Int. Ed. 1986 , 25 , 932-935.
- 8. Hexadeoxynucleotide Self-Replication Kiedrowski, G. Angew. Chem. Int. Ed. 1986 , 25 , 932-935.
- 9. Hexadeoxynucleotide Self-Replication P = 0.48 ɛ = ~25 Kiedrowski, G. Angew. Chem. Int. Ed. 1986 , 25 , 932-935. 0 mM Template 0.2 mM Template 0.4 mM Template 0.8 mM Template
- 10. RNA Ligase Self-Replication Paul, N.; Joyce, G. F. Proc. Natl. Acad. Sci. U. S. A. 2002 , 99 , 12733-40.
- 11. RNA Ligase Self-Replication Paul, N.; Joyce, G. F. Proc. Natl. Acad. Sci. U. S. A. 2002 , 99 , 12733-40.
- 12. RNA Ligase Self-Replication P = ~1 ɛ = 3.0*10 8 Paul, N.; Joyce, G. F. Proc. Natl. Acad. Sci. U. S. A. 2002 , 99 , 12733-40.
- 13. Peptide Self-Replication Lee, D. H.; Granja, J. R.; Martinez, J. A.; Severin, K.; Ghadri, M. R. Nature 1996 , 382 , 525-8.
- 14. Peptide Self-Replication Lee, D. H.; Granja, J. R.; Martinez, J. A.; Severin, K.; Ghadri, M. R. Nature 1996 , 382 , 525-8.
- 15. 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 Template 10 uM Template 20 uM Template 40 uM Template P = ~0.5 ɛ = ~500
- 16. Peptide Self-Replication Modifications: Shorter Template Issac, R.; Chmielewski, J. J. Am. Chem. Soc. 2002 , 124 , 6808-9. P=0.91 ɛ=1.0*10 5 Proline “kink” substitution Li, X.; Chmielewski, J. J. Am. Chem. Soc. 2003 , 125 , 11820-1. P=0.91 ɛ=3.2*10 4
- 17. 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.
- 18. Small Molecule Self-Replication 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. +
- 19. 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. P = ~0.5 ɛ = ~22 A + B T
- 20. Small Molecule Self-Replication Terfort, A.; Kiedrowski, G. Angew. Chem. Int. Ed. 1992 , 31 , 654-656.
- 21. Small Molecule Self-Replication Terfort, A.; Kiedrowski, G. Angew. Chem. Int. Ed. 1992 , 31 , 654-656.
- 22. Small Molecule Self-Replication Terfort, A.; Kiedrowski, G. Angew. Chem. Int. Ed. 1992 , 31 , 654-656. P = ~0.5 ɛ = ~16.4 0 Equiv. Template 0.1 Equiv. Template 0.2 Equiv. Template 0.4 Equiv. Template
- 23. Small Molecule Self-Replication 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.
- 24. Small Molecule Self-Replication Pearson, R. J.; Kassianidis, E.; Slawin, A. M.; Philp, D. Org. Biomol. Chem. 2004 , 2 , 3434-41. A + B T 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. +
- 25. Small Molecule Self-Replication 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. P = ~0.1 ɛ = ~8
- 26. Cleavage Based Self-Replication Rather then bond making, active self-replicators are triggered by bond breaking No Product Inhibition (P = 1) A + A A•A A
- 27. Cross-Catalytic Ribozymes Levy, M.; Ellington, A. D. Proc. Natl. Acad. Sci. U. S. A. 2003 , 100 , 6416-6421.
- 28. Cross-Catalytic Ribozymes Levy, M.; Ellington, A. D. Proc. Natl. Acad. Sci. U. S. A. 2003 , 100 , 6416-6421. P = 1 ɛ = 1.2*10 9
- 29. Autopoiesis A Compartment that catalyses the construction of more compartments.
- 30. 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.
- 31. 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.
- 32. 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.
- 33. Locational Self-Replication Free Molecule X Can Catalyze the release of molecule X from Compartment A X X X X X X X X X X X X + X
- 34. 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.
- 35. 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.
- 36. 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*
- 37. Hybridization Chain Reaction (HCR) + Dirks, R. M.; Pierce, N. A. Proc. Natl. Acad. Sci. U. S. A. 2004 , 101 , 15275-8. B’ A’ B’ B A’ C’ + B’ B C A
- 38. 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. A* A (A* • A*•) n
- 39. 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!