A Multiscale Algorithm for Spatiotemporal Modeling of Multivalent Protein–Protein Interaction

Shahinuzzaman,; Barua, Dipak

doi:10.1089/cmb.2017.0178

Cited by 2 publications

(3 citation statements)

References 17 publications

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“…To the best of our knowledge, this work introduces the first spatio-temporal model of multivalent ligand-mediated Fc ɛ RI assembly in the cell membrane. The BD-based simulation approach used in the model is based on our recent work where we studied a generic multivalent ligand-receptor interaction [ 17 ]. The simulation approach explicitly accounts for the coarse-grained structure of the time-evolving species, their diffusion, and steric collisions.…”

Section: Discussionmentioning

confidence: 99%

“…The time adaptive feature is included to accelerate computation, especially in the dilute regimes. The algorithm is based on our recent work [ 17 ]. It selects the time step sizes adaptively to facilitate computation while capturing the site-specific interactions of the species at the sub-nanometre resolution.…”

Section: Methodsmentioning

confidence: 99%

“…Therefore, we adopted a Brownian dynamics (BD)-based approach. To leverage computation, we implemented a time-adaptive feature in the BD simulation algorithm based on our recent work [ 17 ]. We integrated the time-adaptive BD algorithm with an agent-based framework, where we used spatial graphs to define the coarse-grained structures (site-specific features) of the trivalent ligand and bivalent Fc ɛ RI molecules in a two-dimensional plane (cell membrane).…”

Section: Introductionmentioning

confidence: 99%

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A spatio-temporal model reveals self-limiting FcɛRI cross-linking by multivalent antigens

2018

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Aggregation of cell surface receptor proteins by multivalent antigens is an essential early step for immune cell signalling. A number of experimental and modelling studies in the past have investigated multivalent ligand-mediated aggregation of IgE receptors (FcɛRI) in the plasma membrane of mast cells. However, understanding of the mechanisms of FcɛRI aggregation remains incomplete. Experimental reports indicate that FcɛRI forms relatively small and finite-sized clusters when stimulated by a multivalent ligand. By contrast, modelling studies have shown that receptor cross-linking by a trivalent ligand may lead to the formation of large receptor superaggregates that may potentially give rise to hyperactive cellular responses. In this work, we have developed a Brownian dynamics-based spatio-temporal model to analyse FcɛRI aggregation by a trivalent antigen. Unlike the existing models, which implemented non-spatial simulation approaches, our model explicitly accounts for the coarse-grained site-specific features of the multivalent species (molecules and complexes). The model incorporates membrane diffusion, steric collisions and sub-nanometre-scale site-specific interaction of the time-evolving species of arbitrary structures. Using the model, we investigated temporal evolution of the species and their diffusivities. Consistent with a recent experimental report, our model predicted sharp decay in species mobility in the plasma membrane in response receptor cross-linking by a multivalent antigen. We show that, due to such decay in the species mobility, post-stimulation receptor aggregation may become self-limiting. Our analysis reveals a potential regulatory mechanism suppressing hyperactivation of immune cells in response to multivalent antigens.

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Section: Discussionmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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A spatio-temporal model reveals self-limiting FcɛRI cross-linking by multivalent antigens

2018

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Applying Multivalent Biomolecular Interactions for Biosensors

Choi

Jung

2018

Chemistry A European J

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Multivalent interactions between more than one interconnected biomolecule are easily found in diverse natural systems. With the cooperation of many interacting pairs, this clustered binding can achieve highly enhanced affinities. Whereas the binding of an individual pair remains reversible, the binding between multivalent biomolecules can become nearly irreversible. Although the underlying principles of the multivalent effect have yet to be revealed, this intriguing concept of multivalent interaction has been widely applied to diverse fields. Multivalency has become a key strategy to increase the potency of inhibitors against target pathogens and, more recently, enhanced target binding by multivalency has offered an attractive strategy for biosensing. In this article, the current status of multivalent interaction studies and their progress in the biosensing area will be discussed.

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A Multiscale Algorithm for Spatiotemporal Modeling of Multivalent Protein–Protein Interaction

Cited by 2 publications

References 17 publications

A spatio-temporal model reveals self-limiting FcɛRI cross-linking by multivalent antigens

A spatio-temporal model reveals self-limiting FcɛRI cross-linking by multivalent antigens

Applying Multivalent Biomolecular Interactions for Biosensors

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