Influence of length and flexibility of spacers on the binding affinity of divalent ligands

Abstract

SummaryWe present a quantitative model for the binding of divalent ligand–receptor systems. We study the influence of length and flexibility of the spacers on the overall binding affinity and derive general rules for the optimal ligand design. To this end, we first compare different polymeric models and determine the probability to simultaneously bind to two neighboring receptor binding pockets. In a second step the binding affinity of divalent ligands in terms of the IC50 value is derived. We find that a divalent ligand has the potential to bind more efficiently than its monovalent counterpart only, if the monovalent dissociation constant is lower than a critical value. This critical monovalent dissociation constant depends on the ligand-spacer length and flexibility as well as on the size of the receptor. Regarding the optimal ligand-spacer length and flexibility, we find that the average spacer length should be equal or slightly smaller than the distance between the receptor binding pockets and that the end-to-end spacer length fluctuations should be in the same range as the size of a receptor binding pocket.

A Comprehensive Evaluation of the Activity and Selectivity Profile of Ligands for RGD-binding Integrins

“…Ideally, by using the right anchoring point in the molecule, the loss of activity upon functionalization is low. Nevertheless, the size, lipophilicity, and other parameters like the rigidity of the functional as well as the spacing unit can influence the binding of the bioactive moiety to its target9899. To estimate the influence on the IC 50 -values after modification of the ligand, five compounds were chosen as examples (Table 2).…”

Multivalent Thiosialosides and Their Synergistic Interaction with Pathogenic Sialidases

“…To evaluate the possibility of reaching such a chelation on CAT+CBM, we designed divalent sialosides 2 – 8 by using different sized polyethylene glycol (PEG) linkers (from n =2 to 130, Figure a). The largest length, n =130, was within 5 % of the theoretically maximal multivalent effect according to the statistical physics model, which assumes a Gaussian chain for polymers (Figure S1, Supporting Information) . The effective length of the PEG spacers in solution is much shorter than the extended conformation and is proportional to the root‐mean square of the molecular weight of PEG .…”

“…The largestl ength, n = 130, wasw ithin 5% of the theoreticallym aximal multivalent effect according to the statistical physics model,w hich assumes aG aussianc hain for polymers ( Figure S1, Supporting Information). [18] The effective length of the PEG spacers in solution is much shorter than the extended conformation and is proportional to the root-mean square of the molecular weight of PEG. [13] Using this polymer theory,w ee mpirically estimated the averages ugar distances for 2-8,w hich varies from 12 to 67 .…”

Epitope‐Targeted Macrocyclic Peptide Ligand with Picomolar Cooperative Binding to Interleukin‐17F

“…Cooperative binders can be characterized by a loss of binding entropy, but that loss can be more than compensated by gains in binding enthalpy . Liese and Netz used a statistical physics model to predict that the chemical bridge connecting two ligands should be equal or slightly smaller than the distance between the two binding pockets . For the case of IL‐17F, information on the folded structure of the protein, plus knowledge of the preferred orientation of the L F 1 and L F 2 ligands, suggested an optimal linker length.…”