Simple biochemical networks allow accurate sensing of multiple ligands with a single receptor

Singh, Vijay; Nemenman, Ilya

doi:10.1371/journal.pcbi.1005490

Cited by 30 publications

(27 citation statements)

References 43 publications

(120 reference statements)

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“…In nature, it is difficult to definitely know if a trait is a spandrel without detailed historical data and comparisons [33]. Other possibilities could be that absolute discrimination has been selected in conjunction with other properties (such as information transmission [34,35] or statistical decision [36]). But fundamentally, the presence of phenotypic spandrel here is due to the non-trivial computation performed by the cell to disentangle two parameters naturally tied by standard ligand-receptor interactions: kinetic of binding and ligand concentration.…”

Section: Addition Ofmentioning

confidence: 99%

Phenotypic spandrel: absolute discrimination and ligand antagonism

François

Johnson

Saunders

2016

Preprint

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We consider the general problem of absolute discrimination between categories of ligands irrespective of their concentration. An instance of this problem is immune discrimination between self and not-self. We connect this problem to biochemical adaptation, and establish that ligand antagonism -the ability of sub threshold ligands to negatively impact response -is a necessary consequence of absolute discrimination.Thus antagonism constitutes a "phenotypic spandrel": a phenotype existing as a necessary by-product of another phenotype. We exhibit a simple analytic model of absolute discrimination displaying ligand antagonism, where antagonism strength is linear in distance from threshold. This contrasts with proofreading based models, where antagonism vanishes far from threshold and thus displays an inverted hierarchy of antagonism compared to simple model . The phenotypic spandrel studied here is expected to structure many decision pathways such as immune detection mediated by TCRs and Fc RIs.

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Section: Addition Ofmentioning

confidence: 99%

Phenotypic spandrel: absolute discrimination and ligand antagonism

François

Johnson

Saunders

2016

Preprint

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“…I thank A. Walczak for her helpful comments on the manuscript. While this article was under review, a paper treating a similar topic was submitted to the arXiv [37]. Appendix A: Cramér-Rao bound…”

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confidence: 99%

Physical Limit to Concentration Sensing Amid Spurious Ligands

Mora

2015

Phys. Rev. Lett.

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To adapt their behaviour in changing environments, cells sense concentrations by binding external ligands to their receptors. However, incorrect ligands may bind nonspecifically to receptors, and when their concentration is large, this binding activity may interfere with the sensing of the ligand of interest. Here, I derive analytically the physical limit to the accuracy of concentration sensing amid a large number of interfering ligands. A scaling transition is found when the mean bound time of correct ligands is twice that of incorrect ligands. I discuss how the physical bound can be approached by a cascade of receptor states generalizing kinetic proof-reading schemes.Because of their small sizes, biological systems typically operate with only a few copies of the molecules they sense and communicate with. In their pioneering work, Berg and Purcell derived the fundamental bound that the noise arising from these small numbers sets on the accuracy of concentration sensing [1]. Experimental progress in the characterization of single-cell variability [2] and sensing precision [3] has fueled a renewed interest in small-number noise and its implications for information processing [4][5][6]. General or refined bounds on sensing accuracy have been recently derived for single receptors [7][8][9], and extended to spatial [10][11][12][13][14] or temporal [15] gradient sensing, while the metabolic cost and trade-offs of sensing accuracy have been explored [16][17][18][19][20][21][22][23][24][25]. Much of this past work has assumed perfect specificity between the biological receptors and their cognate ligands. In realistic biological contexts, large numbers of spurious ligands may bind receptors nonspecifically, interfering with the ligand of interest [26]. This is the case in the problem of antigen recognition by T-cell receptors, where cells must react to a small number of specific foreign peptides among a large number of nonspecific selfpeptides [27]. Biochemical network architectures based on kinetic proofreading [28,29] have been shown to provide a solution to the discrimination problem, and have been studied in depth theoretically [26,[30][31][32]. However, no fundamental bound has been derived against which to compare the performance of these solutions, save for Ref.[33] where concepts of statistical decision theory were used to derive the minimal decision time to detect cognate ligands. In this paper I derive the fundamental limit on concentration sensing accuracy and ligand detection error in the presence of a large number of spurious ligands. The maximum likelihood estimate achieving the bound can be implemented biologically by simple networks based on push-pull reactions.Consider a mixture of two ligands, only one of which the biological system wishes to sense. The ligand of interest (hereafter referred to as the correct ligand) is present in concentration c, while the interfering or spurious ligand (called the incorrect ligand) is present in concentration c . The biological unit can sense ligands through N ident...

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“…If there is a high probability of observing ligands just subthresholds, antagonism is helpful to essentially buffer spurious fluctuations of ligands [41], reminiscent of what is observed in olfaction [63]. Finally, some models have recently explored theoretically the possible network topologies maximizing information transmission on ligand mixtures, and have pointed out the need of both proofreading and internal feedbacks [49,57]. There are still many challenges to fully understand early immune response.…”

Section: Beyond Absolute Discrimination?mentioning

confidence: 99%

The Case for Absolute Ligand Discrimination: Modeling Information Processing and Decision by Immune T Cells

François

Altan‐Bonnet

2016

J Stat Phys

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Some cells have to take decision based on the quality of surroundings ligands, almost irrespective of their quantity, a problem we name "absolute discrimination". An example of absolute discrimination is recognition of not-self by immune T Cells. We show how the problem of absolute discrimination can be solved by a process called "adaptive sorting". We review several implementations of adaptive sorting, as well as its generic properties such as antagonism. We show how kinetic proofreading with negative feedback implement an approximate version of adaptive sorting in the immune context. Finally, we revisit the decision problem at the cell population level, showing how phenotypic variability and feedbacks between population and single cells are crucial for proper decision.

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Simple biochemical networks allow accurate sensing of multiple ligands with a single receptor

Cited by 30 publications

References 43 publications

Phenotypic spandrel: absolute discrimination and ligand antagonism

Phenotypic spandrel: absolute discrimination and ligand antagonism

Physical Limit to Concentration Sensing Amid Spurious Ligands

The Case for Absolute Ligand Discrimination: Modeling Information Processing and Decision by Immune T Cells

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