Uncovering
the Selection Criteria for the Emergence
of Multi-Building-Block Replicators from Dynamic Combinatorial Libraries
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Abstract
A family of self-replicating macrocycles
was developed using dynamic
combinatorial chemistry. Replication is driven by self-assembly of
the replicators into fibrils and relies critically on mechanically
induced fibril fragmentation. Analysis of separate dynamic combinatorial
libraries made from one of six peptide-functionalized building blocks
of different hydrophobicity revealed two selection criteria that govern
the emergence of replicators from these systems. First, the replicators
need to have a critical macrocycle size that endows them with sufficient
multivalency to enable their self-assembly into fibrils. Second, efficient
replication occurs only for library members that are of low abundance
in the absence of a replication pathway. This work has led to spontaneous
emergence of replicators with unrivalled structural complexity, being
built from up to eight identical subunits and reaching a MW of up
to 5.6 kDa. The insights obtained in this work provide valuable guidance
that should facilitate future discovery of new complex self-replicating
molecules. They may also assist in the development of new self-synthesizing
materials, where self-assembly drives the synthesis of the very molecules
that self-assemble. To illustrate the potential of this concept, the
present system enables access to self-assembling materials made from
self-synthesizing macrocycles with tunable ring size ranging from
trimers to octamers