Dissecting the molecular determinants of ligand-binding-induced macromolecular switching using thermodynamic cycles.

The energetic networks that govern regulated switching processes in macromolecules are poorly understood at a molecular level. We illustrate a general methodology that uses thermodynamic cycles to measure the coupling energetics between specific groups in a macromolecule and ligand-binding-induced macromolecular switching. The approach is applied to new and published thermodynamic stability and/or binding data not previously analyzed in this way, for a wide range of switching systems, including H+ or Ca²+-binding-induced myristoyl switching, ion or peptide-binding-induced conformational switching in various proteins and small molecule binding to a ribo-switch. The results show how this powerful approach can be used to identify and dissect the molecular determinants of switching in macromolecules.