Computational Insights Into Avidity of Polymeric Multivalent Binders

Abstract

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 and size, and 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 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 inter-target 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.

Designing enhanced entropy binding in single-chain nano particles

“…Being the number of bonds (and hence the energy) the same in both phases, entropy becomes the only driving force for condensation [12]. Functionalized polymers, in which a fraction of the monomers are able to form reversible bonds, have recently entered the radar of the soft-matter [13][14][15][16][17][18][19][20][21] and biophysics [22][23][24][25][26] communities, and experimentally synthesised even inside cells to promote gelation [27]. If the chain flexibility is large enough and the associative monomers can form only single bonds, then at low density bonding takes place essentially within the same polymer, forming soft nano-objects named single-chain nanoparticles (SCNP) [17].…”