Balancing specificity, sensitivity, and speed of ligand discrimination by zero-order ultraspecificity

Abstract

Specific interactions between receptors and their target ligands in the presence of non-target ligands are crucial for biological processes such as T cell ligand discrimination. To discriminate between the target and non-target ligands, cells have to increase specificity by amplifying the small differences in affinity among ligands. In addition, sensitivity to ligand concentration and quick discrimination are also important to detect low amounts of target ligands and facilitate fast cellular decision making after ligand recognition. In this work, we find that ultraspecificity is naturally derived from a well-known mechanism for zero-order ultrasensitivity to concentration. We also show that this mechanism can produce an optimal balance of specificity, sensitivity, and quick discrimination. Furthermore, we show that a model for insensitivity to large number of non-terget ligands can be naturally derived from the ultraspecificity model. Zero-order ultraspecificity may provide alternative way to understand ligand discrimination from the viewpoint of the nonlinear properties of biochemical reactions.

Ultrasensitive molecular controllers for quasi-integral feedback

“…The input w can be used to easily tune the output response threshold. A push-pull motif of a covalent modification cycle was reported to achieve zero-order ultrasensitivity in vitro [38], although this behavior is hard to find in nature [36]. This mechanism satisfies our two of the requirements for quasi-integral action (ultrasensitivity and tunable threshold).…”

Ultrasensitive molecular controllers for quasi-integral feedback

“…The input w can be used to easily tune the output response threshold. A push-pull motif of a covalent modification cycle was reported to achieve zero-order ultrasensitivity in vitro (Kajita et al, 2017), although this behavior is hard to find in nature (Goldbeter and Koshland, 1981). This mechanism satisfies the requirements discussed here for quasi-integral action (ultrasensitivity and tunable threshold).…”

Identifying feasible operating regimes for early T-cell recognition: The speed, energy, accuracy trade-off in kinetic proofreading and adaptive sorting

“…For the biologically realistic 100 s window for making immune recognition, the KPR cascade achieves a respectable error rate between 10 −3 and 10 −4 whereas the adaptive sorting circuit is essentially non-functional. For this reason, it is also interesting to consider other mechanisms for balancing speed and accuracy [ 55 ].…”