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Computational Insights into Avidity of Polymeric Multivalent Binders.

08:00 EDT 24th July 2019 | BioPortfolio

Summary of "Computational Insights into Avidity of Polymeric Multivalent Binders."

Multivalent binding interactions are commonly found throughout biology to enhance weak monovalent binding such as between glycoligands and protein receptors. Designing multivalent polymers to bind to viruses and toxic proteins is a promising avenue for inhibiting their attachment and subsequent infection of cells. Several studies have focused on oligomeric multivalent inhibitors and how changing parameters such as ligand shape, size, linker length, and flexibility affect binding. However, experimental studies of how larger structural parameters of multivalent polymers, such as degree of polymerization, affect binding avidity to targets have mixed results, with some finding an improvement with longer polymers and some finding no effect. Here, we use Brownian dynamics simulations to provide a theoretical understanding of how the degree of polymerization affects the binding avidity of multivalent polymers. We show that longer polymers increase binding avidity to multivalent targets but reach a limit in binding avidity at high degrees of polymerization. We also show that when interacting with multiple targets simultaneously, longer polymers are able to use intertarget interactions to promote clustering and improve binding efficiency. We expect our results to narrow the design space for optimizing the structure and effectiveness of multivalent inhibitors as well as be useful to understand biological design strategies for multivalent binding.

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This article was published in the following journal.

Name: Biophysical journal
ISSN: 1542-0086
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Medical and Biotech [MESH] Definitions

A 15 kD "joining" peptide that forms one of the linkages between monomers of IMMUNOGLOBULIN A or IMMUNOGLOBULIN M in the formation of polymeric immunoglobulins. There is one J chain per one IgA dimer or one IgM pentamer. It is also involved in binding the polymeric immunoglobulins to POLYMERIC IMMUNOGLOBULIN RECEPTOR which is necessary for their transcytosis to the lumen. It is distinguished from the IMMUNOGLOBULIN JOINING REGION which is part of the IMMUNOGLOBULIN VARIABLE REGION of the immunoglobulin light and heavy chains.

Specialized Fc receptors (RECEPTORS, FC) for polymeric immunoglobulins, which mediate transcytosis of polymeric IMMUNOGLOBULIN A and IMMUNOGLOBULIN M into external secretions. They are found on the surfaces of epithelial cells and hepatocytes. After binding to IMMUNOGLOBULIN A, the receptor-ligand complex undergoes endocytosis, transport by vesicle, and secretion into the lumen by exocytosis. Before release, the part of the receptor (SECRETORY COMPONENT) that is bound to IMMUNOGLOBULIN A is proteolytically cleaved from its transmembrane tail. (From Rosen et al., The Dictionary of Immunology, 1989)

Polymeric materials (usually organic) of large molecular weight which can be shaped by flow. Plastic usually refers to the final product with fillers, plasticizers, pigments, and stabilizers included (versus the resin, the homogeneous polymeric starting material). (McGraw-Hill Dictionary of Scientific and Technical Terms, 4th ed)

Usually inert substances added to a prescription in order to provide suitable consistency to the dosage form. These include binders, matrix, base or diluent in pills, tablets, creams, salves, etc.

Quantitative determination of receptor (binding) proteins in body fluids or tissue using radioactively labeled binding reagents (e.g., antibodies, intracellular receptors, plasma binders).

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