Quantitative analysis of affinity enhancement by noncovalently oligomeric ligands.
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.
Department of Pharmaceutical Sciences, Washington State University, Pullman, WA 99164, USA. gpoon@wsu.edu
Gregory M K
GM
Poon
D008024:Ligands; D008958:Models, Molecular; D010767:Phosphorylcholine / Q000737:chemistry / Q000378:metabolism; D058105:Polymerization; D011485:Protein Binding; D055503:Protein Multimerization; D020836:Protein Structure, Quaternary; D057127:Single-Chain Antibodies / Q000378:metabolism; D013379:Substrate Specificity; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism; D016159:Tumor Suppressor Protein p53 / Q000737:chemistry / Q000378:metabolism
D008024:Ligands; D057127:Single-Chain Antibodies; D014409:Tumor Necrosis Factor-alpha; D016159:Tumor Suppressor Protein p53; D010767:Phosphorylcholine