Abstract:
:Equilibrium binding ligands usually increase protein thermal stability by an amount proportional to the concentration and affinity of the ligand. High-throughput screening for the discovery of drug-like compounds uses an assay based on thermal stabilization. The mathematical description of this stabilization is well developed, and the method is widely applicable to the characterization of ligand-protein binding equilibrium. However, numerous cases have been experimentally observed where equilibrium binding ligands destabilize proteins, i.e., diminish protein melting temperature by an amount proportional to the concentration and affinity of the ligand. Here, we present a thermodynamic model that describes ligand binding to the native and unfolded (denatured) protein states explaining the combined stabilization and destabilization effects. The model also explains nonsaturation and saturation effects on the protein melting temperature when the ligand concentration significantly exceeds the protein concentration. Several examples of the applicability of the model are presented, including specific sulfonamide binding to recombinant hCAII, peptide and ANS binding to the Polo-box domain of Plk1, and zinc ion binding to the recombinant porcine growth hormone. The same ligands may stabilize and destabilize different proteins, and the same proteins may be stabilized and destabilized by different ligands.
journal_name
Biophys Jjournal_title
Biophysical journalauthors
Cimmperman P,Baranauskiene L,Jachimoviciūte S,Jachno J,Torresan J,Michailoviene V,Matuliene J,Sereikaite J,Bumelis V,Matulis Ddoi
10.1529/biophysj.108.134973subject
Has Abstractpub_date
2008-10-01 00:00:00pages
3222-31issue
7eissn
0006-3495issn
1542-0086pii
S0006-3495(08)78464-9journal_volume
95pub_type
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