Uncovering the selection criteria for the emergence of multi-building-block replicators from dynamic combinatorial libraries. 
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.