Dynamic equilibrium within a library of amphiphilic β-sheet peptides driven by template selectivity

Molecular self-assembly of β-sheet forming peptides has been proposed as the driving force for the emergence of early enzymes and information-preserving replication. The ability to replicate and evolve is fundamental to all living systems and is a key feature of the current β-sheet model. Presently, β-sheet peptides are known to form amyloid-aggregates which have been found to be stably folded, information-preserving, and auto-catalytic. Thus, they have been proposed to be the first molecular replicator on primitive earth.

The current research presents a system based on short amphiphilic β-sheet forming peptides which react through thiol-thioester exchange reaction (TTE). In this system, an electrophilic peptide (L/D) becomes activated as a thioester, subsequently is attacked by a nucleophilic thiol-peptide. The final products will contain thioester bond which could later be detached and reformed via nucleophilic attacks. Our results demonstrate a functioning self-assembling system, in which ligation of thioester electrophile and thiol-nucleophile (the “forward” reaction) produces 4 epi/isomeric products. The “reverse” reaction, initiated with just one of the isomers (the full-length thioester products) and a nucleophile, also shown to form all 4 epi/isomers, even in control experiments containing only one isomer with no additional reaction components. The reversibility of the system allows recycling of building blocks and “error correction” within its pathways. A more dominant effect of template presence is notable in the beginning of kinetic experiment procedure (thus farther from equilibrium). Competition trends are under investigation in the present. β-sheet formations seem to be paramount to these kinds of systems.

The reversible nature of the system allows selectivity in product formation, that may be viewed as a model for early evolution. Moreover, the systems chemistry approach attempts to capture the complexity and emergent phenomena prevalent in the life sciences within a wholly synthetic chemical framework.