Allostery in protein systems is a thermodynamic phenomenon. The binding of an effector (ligand) at one site in the protein, results in an apparent change in binding affinity at a different ligand binding site. The net result is that proteins are often able to greatly increase their activity in response to small changes in effector concentration.
While traditional views of allostery have concentrated on structural changes induced by the binding of ligands (i.e. "enthalpically dominated"), it is now increasingly recognised that fluctuations in structure can contribute to allosteric regulation. In some cases, where ligand-induced structural changes are absent, thermal fluctuations can play a dominant role in determining allosteric signalling. In thermodynamic terms, the entropy change for subsequent binding is influenced by global vibrational modes being either damped or activated by an initial binding event. One advantage of such a mechanism (in nature) is the possibility for long range allosteric signalling. Here, changes to slow internal motion can be harnessed to provide signalling across long distances.
This talk employs a multiscale approach to understand “dynamic allostery” focussing particularly on the homodimeric catabolite activator protein (CAP). Results are obtained from atomistic simulations, simple coarse-grained models, and super-coarse-grained models designed to show how fluctuations can play a key role in allosteric signaling.
Results are presented for atomistic normal mode analysis, and principle component analysis, exemplified by the binding of cAMP to CAP. These results are compared to an elastic network model and a super-coarse-grained model based on a simplified network of springs. We show that these simple models of dynamics are predictive in terms of understanding dynamic allostery. We demonstrate also that the sign of the allosteric response can be controlled by selective mutation of amino acids far removed from the ligand binding sites. The predicted “control by third site mutation”, has recently been verified by experimental binding studies.
Finally, we provocatively suggest that proteins may have evolved to take advantage of the thermal environment that they find themselves in, using thermal energy to amplify the effects of ligand binding.
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