| Article ID | Journal | Published Year | Pages | File Type |
|---|---|---|---|---|
| 1174314 | Analytical Biochemistry | 2013 | 9 Pages |
Designed ligands that self-assemble noncovalently via an independent oligomerization domain have demonstrated enhancement in affinity for a variety of chemical and biological targets. To better understand the thermodynamic linkage between enhanced receptor binding and self-assembly, we have developed linkage models for the three commonly encountered types of noncovalently oligomeric ligands: homofunctional oligomeric ligands, heterodimeric ligands that target a single receptor, and bispecific ligands that crosslink noninteracting receptors. Expressions and numerical approaches for exact analysis as a function of total ligand concentrations are provided. We apply the linkage models to the binding data for two published noncovalently oligomeric ligands: one targeting a small molecule (phosphocholine) and the other targeting a soluble protein (tumor necrosis factor α). The linkage models provide a quantitative measure of the potential and realized enhancement in affinity that could inform and guide design optimization efforts, and they reveal physical insight that would elude model-free analysis. Incorporation of the linkage models, therefore, is expected to be valuable in the rational engineering of noncovalently oligomeric ligands.
