Stochastic Yield Catastrophe in Delay-Facilitated Self-Assembly

Self-assembly of supramolecular structures in cells and synthetic applications often proceeds under unfavorable biochemical conditions and at low copy numbers of final target structures, ranging from tens of bacterial microcompartments to a single bacterial flagellum per cell.

Spatial organization through coupled reaction compartments of different reactivity (delay-facilitated assembly) can recover high yield in such environments at the mean-field level, but its robustness to stochastic fluctuations at low target numbers is unclear.

Using stochastic simulations of a minimal two-compartment model, we show that delay-facilitated assembly is susceptible to a stochastic yield catastrophe at low target numbers: even when each compartment in isolation allows for high-yield assembly, slow exchange between them induces a substantial drop in the final yield.

We trace the mechanism to a specific assembly stage, where the random order of rate-limiting exchange events of subunits and partially completed structures determines the ratio of productive growth to excess nucleation.

Restricting the exchange of larger structures -- either by suppressing it entirely or letting exchange rates decrease with size -- restores most of the yield without altering the mean-field behavior.

The same phenomenology appears for two-dimensional hexagonal subunits and in a cytosol-membrane geometry, where diffusion-limited exchange naturally implements the required size dependence.

Our results show that equal success of assembly strategies at high target numbers does not imply their equal success at low target numbers, and that competing slow events occurring in random order are a common signature of stochastic yield catastrophes.