The influence of rigid or flexible linkage between two ligands on the effective affinity and avidity for reversible interactions with bivalent receptors

Abstract

Bivalent or polyvalent cooperative binding between ligand and receptor is much tighter and more efficient than monovalent binding of the same counterparts. Because of this, many biological processes involve polyvalent binding for realization of regulatory mechanisms. For this reason it is necessary to develop a general formalism for prediction of the relationship between the binding affinities of each ligand subunits, the length of the flexible linker between them and avidity of the interaction. Here, we consider an approach that is based on the description of the state of equilibrium for the reaction of mono- and multivalent ligand-receptor binding of algebraic equation systems. This approach allows the evaluation of the avidity of bivalent binding and to determine the concentrations of ligand-receptor complexes, which will be obtained at the equilibrium state. The analysis presented here may be useful in analysing the binding behaviour of a bivalent receptor and a ligand consisting of two subunits covalently connected with a rigid or flexible linker.

Linkage-Specific Avidity Defines the Lysine 63-Linked Polyubiquitin-Binding Preference of Rap80

“…Systems with less flexibility are expected to have higher affinities and specificities because entropic costs are higher when more flexible linkers need to bring binding units together in space, and because flexible linkers do not restrict binding units to a small set of potentially distinguishing conformations. Also, the intrinsic affinities of individual domains contribute to specificity and affinity; because avidity at best only multiplies receptor affinities, weak-binding receptors will gain less from a similar multivalent arrangement than tight ones (Bobrovnik, 2007; Schleif, and Wolberger, 2004). Potentially, UBDs distant in primary sequence, or even on separate polypeptides, could achieve linkage selectivity through avid interactions so long as flexibility between properly positioned domains is minimized.…”

Behaviour of intrinsically disordered proteins in protein–protein complexes with an emphasis on fuzziness

“…This infers that the ratio between the on-rates, k 2 / k 1 , will be the same as that given for the equilibrium constants in Eq (5). Since the linker is disordered, its properties, in terms of dimensions, rigidity and modulation of dynamics and flexibility potentially by post-translational modifications, may influence the avidity by modulating ‹ r › [27, 28]. Once the linker gets too long, the two sites decouple and the cooperativity is lost [25, 27].…”

Multivalent Polymer Nanocomplex Targeting Endosomal Receptor of Immune Cells for Enhanced Antitumor and Systemic Memory Response

“…[2] Because nanoparticles have the intrinsic advantage that identical epitopes can be attached to their surfaces,m ost previous studies have focused on the use of solid spherical nanoparticles with amultivalent targeting ligand for applications in cancer diagnosis and therapy. [4] Although some researchers have also attempted to use virus membranes with am ultivalent hemagglutinin structure as potent vaccine adjuvants to boost the immune response,t he laborious preparation procedures and safety issues associated with these viral membranes limited their widespread use. [4] Although some researchers have also attempted to use virus membranes with am ultivalent hemagglutinin structure as potent vaccine adjuvants to boost the immune response,t he laborious preparation procedures and safety issues associated with these viral membranes limited their widespread use.…”