Assembly theory quantifies directedness in chemical reaction networks
A new paper from the Cronin Group, published in ACS Central Science, shows how assembly theory can be used to measure whether an open-ended chemical system explores chemical space broadly or in a directed way. The team introduces two experimentally accessible metrics: the exploration ratio (ER), which captures how completely a system samples its inferred joint assembly space, and ensemble assembly (A), which combines the assembly index of each observed molecule with its copy number. Using peptide formation as a model system, the researchers polymerised amino acids under nonspecific activation conditions, including robotic wet-dry cycling programmed in χDL and CDI-mediated coupling, and compared these with reactions catalysed by sequence-selective proteases. Nonspecific conditions gave typically exploration ratios of 0.77 to 0.96, while protease-directed reactions gave lower ratios of 0.51 to 0.75 together with elevated ensemble assembly. This was observed across multiple environments and amino acid combinations.
Products were identified by HPLC-MS/MS and annotated with the group’s OLIGOSS software, and bigram analysis confirmed that the proteases impose coordinated selectivity across several residues, consistent with their known substrate preferences. The work establishes ER and A as practical comparative measures of directedness, and provides a route to quantifying selection when combined with time-resolved data or matched controls, with implications for reaction-network analysis, combinatorial synthesis and chemical evolution.
The paper is open access at https://doi.org/10.1021/acscentsci.6c00618