Compatibility constraints for intracellular binding: the case of evolutionary design principles of cellular metal sensors

In a shared cellular space, hundreds of reactions occur reliably and simultaneously without significantly interfering with each other. The evolutionary design principles that enable full compatibility of chemical binding reactions are not well characterized. To uncover these principles, we study the case of transition metal sensing in bacterial cytosol. This is an interesting problem as sensing proteins need to bind to cognate metals that often have a lower binding affinity than competing noncognate metals. Based solely on theoretical considerations and tabulated stability constants for metal-amino acid interactions, we are able to predict, with good accuracy, the amino acid composition of many known bacterial sensor binding-sites. Consistent with experiments, we find that sensor combinations are strongly constrained by theoretically derived compatibility requirements, leaving only a handful of possible sensors for each metal. If applicable to general cytosolic binding interactions, our results would imply that it is crucial to consider compatibility criteria while studying cellular processes. Such an approach could prove beneficial for the understanding of many biological systems and for potential applications.