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conditions when autocatalytic production competes with
conjugate addition in an open reactor is a general phenom-
enon.
Acknowledgements
This work was supported by the Israel Science Foundation
(grant 2333/19, to S.N.S.) and by a research grant from the
Weizmann SABRA—Yeda-Sela—WRC Program, the Estate
of Emile Mimran, and The Maurice and Vivienne Wohl
Biology Endowment. We thank D. Fass and E. Bortnikov for
helpful comments regarding this manuscript.
Conclusion
In this work, we studied autocatalytic oligomerization of
disulfide of tripeptides. This reaction predominantly afforded
macrocyclic products instead of linear oligomers for a broad
range of substrates and even at high concentrations of
substrates. The hopping of the thioester group along the
polymer chain by thiol–thioester exchange is the most likely
reason for this behavior.[20] To the best of our knowledge,
there are no other spontaneous polymerization reactions that
produce macrocyclic peptides as major products. Moreover,
upon oxidation, the products form many internal disulfides
making them conformationally rigid and potentially more
functional than flexible macrocycles.
The autocatalytic reaction network that we described here
is strongly interconnected because of the variety of thiol-
disulfide exchange reactions.[8b,9a] As a result of this con-
nectivity, the autocatalysis is nonspecific for the individual
products;[8c,d,24] all thiols cross-catalyze their own production.
We used this system to study a situation where a nonspecific
autocatalytic reaction is combined in an open compartment
with a removal reaction that prefers “small” to “large”
molecules. In this case, large (3-mer or larger) macrocycles
that conformationally can form unstrained intramolecular
disulfides became major products at the steady state, in
contrast to a system without the removal mechanism, where
dimer was the prevalent product. Interestingly, our experi-
ments (see the Supporting Information, Figure 79) indicate
the preferential formation of the products with saturated
intramolecular disulfides upon oxidation of large cycles. Thus,
we can imagine a situation where one of the macrocycles will
be selected in an open system because its oxidized form will
self-assemble into complex aggregate that would be retained
at flow conditions (e.g. by attachment to surfaces).
Nonspecific autocatalysis is easier to imagine in prebiotic
organic chemistry (e.g., the chemistry of HCN and NH2CN)
than selective self-replication,[25] which requires molecules
capable of specific molecular recognition (e.g., nucleoti-
des).[6b,26] Although it cannot drive Darwinian evolution, an
autocatalytic reaction still can ensure the localization of
reactions in, for instance, some semipermeable compartment
(e.g., a vesicle or coacervate drop) if the starting materials
permeate into and from a compartment easier than an
autocatalyst does.[27] This situation already favors the forma-
tion of large molecules because of their slow diffusion and
thus, their accumulation in the compartment. If, in addition,
parallel removal reactions (e.g., photolysis or hydrolysis) exist
and some of the products are less vulnerable to these
reactions, as large macrocycles in this work that form
intramolecular disulfides that protect them from conjugate
addition, these molecules would be selected and could give
rise to new emergent functionalities and possibly information-
carrying replicators.
Conflict of Interest
The authors declare no conflict of interest.
Keywords: autocatalysis · macrocyclic peptides · origin of life ·
reaction networks · systems chemistry
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&&&&
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