Kinetic studies and modeling of a self-replicating system

Abstract

A close and relevant parallel is the ionization of (the isoelectronic) primary amides. Here too calculations indicate that the 2 isomer (of the anion) is more stable in the gas phase by about 5 kcal/mol.'8 Since the isomeric anions are in equilibrium with the same conjugate acid, this is a direct measure of the difference (1 7) The calculated (>5 kcal/mol) preference of esters for the 2 conformation is also much reduced in solution, as indicated by a measured ("C NMR) value of 1.67 kcal/mol for ethyl formate. (Grindley, T. B. Terrahedron k r t . 1982, 1757-60.) Increasing the size of either the acyl or the alkyl substituent increases the preference for the Z conformation, presumably for steric reasons, so any stereoelectronic preference should be most clearly expressed in formate esters. (18) Zielinski, T. J.; Poirier, R. A.; Peterson, M. R.; Csizmadia, I. G. J . Comput. Chem. 1982, 3, 477-485. Nguyen, N. T.; Hegarty, A. F. J. Org. Chem. 1986, 51. 4703-6. in acidity between the E and 2 protons. In this case it is possible HE :N-W E-anionZ-anion to measure the equilibria, and the proton-transfer processes involved, in solution. In aqueous solvent, the base-catalyzed exchange of H E is never more than a few times faster than that of Hz; the E / Z ratio is strongly solvent-dependent, and under some conditions the solvated E isomer is actually preferred.19 (19) Perrin, C. L.; Johnston, E. R.; Lollo, C. P.; Kobrin, P. A. Abstract:The design, synthesis, and study of a molecular template, 1 la, that catalyzes its own formation from simpler components, 9 and lOd, is described. Autocatalysis is shown by the following: (1) the increase in rate of reaction of 9 and 1Od in the presence of Ila; (2) the reduction in rate of reaction in the presence of 2,6-bis(acetylamino)pyridine inhibitor; and (3) the reduction in rate of reaction when a component incapable of template behavior, 10h, is substituted for 1Od. Three kinetic pathways are elucidated: ( I ) the background bimolecular reaction (eq 6); (2) the preassociative mechanism (eq 7); and (3) the template termolecular process (eq 8). A kinetic model for the replication process is introduced, and equilibrium and rate constants are determined. Predictions for the shapes of the product growth curves are made.Helbing, J.; Mattzen, M.; Jordan, S. Abstract:The stereoselectivity of the intramolecular photocycloaddition of a series of bicyclic dioxenones has been examined.The selective formation of trans-fused photoadducts is observed in almost all cases, which upon fragmentation lead to the synthesis of bicycloalkanones with an 'inside-outside" or trans intrabridgehead stereochemical relationship. This methodology has been applied to the synthesis of several 'inside-outside" bicycloalkanones that cannot otherwise be prepared. The unusual reactivity of both the dioxanone photoadducts and the bicycloalkanone fragmentation products is described.

On the failure of de novo-designed peptides as biocatalysts.

“…Catalytic antibodies, which were originally reported in 1986, can be characterized as antibodies directed against haptens, which are usually synthetic analogs of the transition states of the chemical reactions to be catalyzed. Reengineering of enzymes has been possible in principle since the advent of genetic engineering, more than two decades ago; a review of Medline entries indicated that studies involving site-directed mutagenesis of enzymes for both reengineering and purely investigatory purposes have produced an average of over 280 papers a year since 1990 in the joumals catalogued by Medline.t At the opposite conceptual end of the field, chemists interested in catalysis have selected aspects of enzyme behavior capable of being mimicked in smaller systems and have succeeded in producing catalysts with a number of enzyme-like features (6)(7)(8)(9)(10)(11)(12). Catalytic RNA or "ribozyme" technology (13,14) represents yet another promising area in biocatalysis, but it is still possible that the catalytic capabilities of ribozymes, which necessarily have smaller chemical and structural repertoires available than proteins and general synthetic constructs, will prove to be limited to acyl transfer and hydrolysis reactions; these are both areas in which catalytic antibodies and RNEs are already highly proficient.…”

“…Category 3 is not manifestly impossible, but since mechanisms by which the free energy of association is transduced in natural enzymes are poorly understood, it would be astonishing if this effect could be designed and used efficiently in a de novo-designed molecule until further major advances are made in structure prediction and protein dynamics. Category 4 is the feature most readily available to the biocatalyst designer, and the most successful attempts in this field have made free use of contemporary knowledge of both chemical catalysis and the roles of active site residues in enzymes (6)(7)(8)(9)(10)(11)(12)36); however, as mentioned above, our ability to apply this knowledge effectively is severely limited by our failure, for the most part, to deliver appropriate three-dimensional scaffolds for proper placement of the tools of catalysis. Smaller, disordered peptides may contain all the functional groups of enzyme active sites, but even if the peptide is capable of assuming a catalytic conformation, it is conceivable, given the enormous magnitude of shape space accessible to a peptide of even 30 amino acid residues, that the age of the planet would elapse before the desired conformation were to be assumed (37).…”

“…The difference appears to lie in the fact that peptides of the sizes amenable to solid-phase synthesis and conformational analysis do not generally have fixed structures (99), whereas synthetic organic molecules, with a larger range of small units available as input to the design, can be formed with as many bridging and cyclizing features as desired, providing they are chemically feasible. The most notable successes on the synthetic front have taken full advantage of this capability by creating rigid, cage-like structures, which evidently aid in fixing the positions of the reactive groups of both catalyst and substrate (6)(7)(8)(9)(10)(11)(12).…”

Organoautocatalysis: Challenges for experiment and theory

“…That even much smaller and simpler molecules are capable of exhibiting self-replication, was first shown by Rebek and co-workers for artificial synthetic models ( Figure 1) [10,11].…”

Chemical amplification with encapsulated reagents

“…Although the present system has some phenomenological similarities to autocatalysis, there are important differences. First, templated autocatalysis selects specific molecular products from a sea of reactive possibilities based on their ability to reproduce (15)(16)(17)(18)(19)(20)(21)(22)(23). Traditional autocatalysis involves direct competition of individual molecules.…”