Minimal models of multi-site ligand-binding kinetics

Juška, Alfonsas

doi:10.1016/j.jtbi.2008.08.030

Cited by 11 publications

(8 citation statements)

References 25 publications

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“…The negative rate of complex dissociation will be k -1 times the complex number. The statistical process underneath this assumption relies basically upon a time independent (exponential) undocking probability [36]. …”

Section: Methodsmentioning

confidence: 99%

“…In other words, each receptor of a cluster interacts with ligand localized in the exact same portion of the extracellular vicinity, and clusters of size n can be seen as receptors with n sites. With this assumption, the ODE describing the equilibrium saturation rate of receptors is a special case of equations considering clusters of size n as virtual macromolecules with n docking sites, as seen in [36-38]. This simple trick allows us to compute the number of sites occupied c .…”

Section: Methodsmentioning

confidence: 99%

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Impact of receptor clustering on ligand binding

Caré

Soula

2011

BMC Syst Biol

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BackgroundCellular response to changes in the concentration of different chemical species in the extracellular medium is induced by ligand binding to dedicated transmembrane receptors. Receptor density, distribution, and clustering may be key spatial features that influence effective and proper physical and biochemical cellular responses to many regulatory signals. Classical equations describing this kind of binding kinetics assume the distributions of interacting species to be homogeneous, neglecting by doing so the impact of clustering. As there is experimental evidence that receptors tend to group in clusters inside membrane domains, we investigated the effects of receptor clustering on cellular receptor ligand binding.ResultsWe implemented a model of receptor binding using a Monte-Carlo algorithm to simulate ligand diffusion and binding. In some simple cases, analytic solutions for binding equilibrium of ligand on clusters of receptors are provided, and supported by simulation results. Our simulations show that the so-called "apparent" affinity of the ligand for the receptor decreases with clustering although the microscopic affinity remains constant.ConclusionsChanging membrane receptors clustering could be a simple mechanism that allows cells to change and adapt its affinity/sensitivity toward a given stimulus.

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Section: Methodsmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

Impact of receptor clustering on ligand binding

Caré

Soula

2011

BMC Syst Biol

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“…Higher-order complexes may exist (Smith and Milligan 2010; Juška 2008), and while a general functional signalling model for an -order oligomer may be impractical, a ligand binding model of the type developed in the current work should be possible and may be valuable in distinguishing between orders of oligomer.…”

Section: Discussionmentioning

confidence: 98%

“…Extension to a more general model which will encompass heterodimers will require reversion to the May et al schematic, but with an implicit asymmetry which will allow for an “extra level of complexity” (Bai 2004). Higher-order complexes may exist (Smith and Milligan 2010; Juška 2008), and while a general functional signalling model for an -order oligomer may be impractical, a ligand binding model of the type developed in the current work should be possible and may be valuable in distinguishing between orders of oligomer.Here, we have assumed that all dimeric receptors are constitutively produced, are the only receptor entities and have not considered the dimerisation process itself. However, a mixture of monomers, dimers and higher oligomers may exist (Smith and Milligan 2010; Milligan 2004), and ligand-induced effects on the dimerisation process have also been noted for GPCRs (Smith and Milligan 2010; Bai 2004) and other receptors (Mac Gabhann and Popel 2007).…”

Section: Discussionmentioning

confidence: 99%

“…Within a Hill function analysis, however, there is the possibility that information is missed due to the inability of Hill coefficients to distinguish interaction mechanisms (Prinz 2010). These works appear to be the state of the art in practical GPCR models, while more mathematically abstract approaches are taken elsewhere: an algebra of dimerisation is presented in Woolf and Linderman (2004), and generalised multi-site binding models are analysed in Juška (2008).…”

Section: Introductionmentioning

confidence: 99%

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Ligand Binding Dynamics for Pre-dimerised G Protein-Coupled Receptor Homodimers: Linear Models and Analytical Solutions

White

Bridge

2018

Bull Math Biol

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Evidence suggests that many G protein-coupled receptors (GPCRs) are bound together forming dimers. The implications of dimerisation for cellular signalling outcomes, and ultimately drug discovery and therapeutics, remain unclear. Consideration of ligand binding and signalling via receptor dimers is therefore required as an addition to classical receptor theory, which is largely built on assumptions of monomeric receptors. A key factor in developing theoretical models of dimer signalling is cooperativity across the dimer, whereby binding of a ligand to one protomer affects the binding of a ligand to the other protomer. Here, we present and analyse linear models for one-ligand and two-ligand binding dynamics at homodimerised receptors, as an essential building block in the development of dimerised receptor theory. For systems at equilibrium, we compute analytical solutions for total bound labelled ligand and derive conditions on the cooperativity factors under which multiphasic log dose-response curves are expected. This could help explain data extracted from pharmacological experiments that do not fit to the standard Hill curves that are often used in this type of analysis. For the time-dependent problems, we also obtain analytical solutions. For the single-ligand case, the construction of the analytical solution is straightforward; it is bi-exponential in time, sharing a similar structure to the well-known monomeric competition dynamics of Motulsky-Mahan. We suggest that this model is therefore practically usable by the pharmacologist towards developing insights into the potential dynamics and consequences of dimerised receptors.B Lloyd J. Bridge

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