Memory Switches in Chemical Reaction Space

Just as complex electronic circuits are built from simple Boolean gates, diverse biological functions, including signal transduction, differentiation, and stress response, frequently use biochemical switches as a functional module. A relatively small number of such switches have been described in the literature, and these exhibit considerable diversity in chemical topology. We asked if biochemical switches are indeed rare and if there are common chemical motifs and family relationships among such switches. We performed a systematic exploration of chemical reaction space by generating all possible stoichiometrically valid chemical configurations up to 3 molecules and 6 reactions and up to 4 molecules and 3 reactions. We used Monte Carlo sampling of parameter space for each such configuration to generate specific models and checked each model for switching properties. We found nearly 4,500 reaction topologies, or about 10% of our tested configurations, that demonstrate switching behavior. Commonly accepted topological features such as feedback were poor predictors of bistability, and we identified new reaction motifs that were likely to be found in switches. Furthermore, the discovered switches were related in that most of the larger configurations were derived from smaller ones by addition of one or more reactions. To explore even larger configurations, we developed two tools: the “bistabilizer,” which converts almost-bistable systems into bistable ones, and frequent motif mining, which helps rank untested configurations. Both of these tools increased the coverage of our library of bistable systems. Thus, our systematic exploration of chemical reaction space has produced a valuable resource for investigating the key signaling motif of bistability.Author Summary: How does a cell know what type of cell it is supposed to become? How do external chemical signals change the underlying “state” of the cell? How are response pathways triggered on the application of a stress? Such questions of differentiation, signal transduction, and stress response, while seemingly diverse, all pertain to the storage of state information, or “memory,” by biochemical switches. Just as a computer memory unit can store a bit of 0 or 1 through electrical signals, a biochemical switch can be in one of two states, where chemical signals are on or off. This lets the cell record the presence/absence of an environmental stimulus, the level of a signaling molecule, or the result of a cell fate decision. There are a small number of published ways by which a group of chemical reactions come together to realize a switch. We undertook an exhaustive computational exploration to see if chemical switches are indeed rare and found, surprisingly, that they are actually abundant, highly diverse, but related to one another. Our catalog of switches opens up new bioinformatics approaches to understanding cellular decision making and cellular memory.