| Protein function is a dynamic phenomenon. It is now increasingly recognised that fluctuations in structure can contribute to allosteric regulation in protein systems. Allosteric response is driven by the free energy differences obtained in different binding events; which, is a balance between enthalpic and entropic changes. In some cases, where ligand-induced structural changes are small, thermal fluctuations can play a dominant role in determining allosteric signalling (i.e “entropically dominated”); which is different from the traditional view of allostery caused by structural changes induced by the binding of ligands (i.e. “enthalpically dominated”). In thermodynamic terms, the entropy change for subsequent binding is influenced by changes to the global vibrational modes of the protein-ligand systems. One advantage of such a mechanism is the possibility for long range allosteric signalling due to modes being either damped or activated by binding events. Changes to slow internal motion can be harnessed to provide signalling across long distances. This paper considers homotropic allostery in homodimeric proteins, and presents results from atomistic simulations and simple course-grained models. These demonstrate that changes in the protein motion plays a key role in allosteric signalling. Results are presented for normal mode analysis, principle component analysis, and elastic network models exemplified by the binding of cAMP to the catabolite activator protein (CAP) |
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