self-replicating molecules: an introduction
DESCRIPTION
A brief Introduction/minireview of self-replicating molecules presented at TSRI Chemistry journal club on 5/11/07. Most of the description was spoken, so slides may seem sparse without verbal explanation, but I though it was worth sharing anyway.TRANSCRIPT
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*unpublished work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.
Hexadeoxynucleotide Self-Replication
Kiedrowski, G. Angew. Chem. Int. Ed. 1986, 25, 932-935.
Hexadeoxynucleotide Self-Replication
0 mM Template
0.2 mM Template0.4 mM Template0.8 mM Template
P = 0.48
ɛ = ~25
Kiedrowski, G. Angew. Chem. Int. Ed. 1986, 25, 932-935.
RNA Ligase Self-Replication
Paul, N.; Joyce, G. F. Proc. Natl. Acad. Sci. U. S. A. 2002, 99, 12733-40.
RNA Ligase Self-Replication
Paul, N.; Joyce, G. F. Proc. Natl. Acad. Sci. U. S. A. 2002, 99, 12733-40.
RNA Ligase Self-Replication
P = ~1
ɛ = 3.0*108
Paul, N.; Joyce, G. F. Proc. Natl. Acad. Sci. U. S. A. 2002, 99, 12733-40.
Peptide Self-Replication
Lee, D. H.; Granja, J. R.; Martinez, J. A.; Severin, K.; Ghadri, M. R. Nature 1996, 382, 525-8.
Peptide Self-Replication
Lee, D. H.; Granja, J. R.; Martinez, J. A.; Severin, K.; Ghadri, M. R. Nature 1996, 382, 525-8.
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
Peptide Self-Replication
• 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.
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.
+
Small Molecule Self-Replication
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.
Small Molecule Self-Replication
Terfort, A.; Kiedrowski, G. Angew. Chem. Int. Ed. 1992, 31, 654-656.
Small Molecule Self-Replication
Terfort, A.; Kiedrowski, G. Angew. Chem. Int. Ed. 1992, 31, 654-656.
Small Molecule Self-Replication
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
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.
Small Molecule Self-Replication
Pearson, R. J.; Kassianidis, E.; Slawin, A. M.; Philp, D. Org. Biomol. Chem. 2004, 2, 3434-41.
A + BT
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.
+
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
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
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
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.
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!