Targeting disordered proteins with small molecules using entropy.
The human proteome includes many disordered proteins. Although these proteins are closely linked with a range of human diseases, no clinically approved drug targets them in their monomeric forms. This situation arises, at least in part, from the current lack of understanding of the mechanisms by which small molecules bind proteins that do not fold into well-defined conformations. To explore possible solutions to this problem, we discuss quite generally how an overall decrease in the free energy associated with intermolecular binding can originate from different combinations of enthalpic and entropic contributions. We then consider more specifically a mechanism of binding by which small molecules can affect the conformational space of a disordered protein by creating an entropic expansion in which more conformations of the protein become populated.
Department of Chemistry, University of Cambridge, Cambridge, UK.
Gabriella T
GT
Heller
Department of Chemistry, University of Cambridge, Cambridge, UK.
Pietro
P
Sormanni
Department of Chemistry, University of Cambridge, Cambridge, UK. Electronic address: mv245@cam.ac.uk.
Michele
M
Vendruscolo
D019277:Entropy; D011485:Protein Binding; D011487:Protein Conformation; D011506:Proteins / Q000737:chemistry*; D013816:Thermodynamics
D011506:Proteins
binding; disordered proteins; entropic expansion; entropy; small molecule