For some time thermophilic proteins have been considered more rigid than their mesophilic homologues. The "rigidity paradigm" was introduce to explain both the extreme stability of thermophiles as well as their lack of activity at ambient conditions. According to this view functionality is then recovered at the high optimal growth temperature because of the activation of the protein flexibility. Experimentally, one of the strongest support to this "corresponding states" picture comes from H/D exchange experiments, see this beautiful comment from R. Jaenicke in PNAS(2000). However, recent works using the H/D exchange, Neutron Scattering and NMR techniques have questioned the paradigm. Inspired by this querelle we have used extensive MD simulations to play with the concept for a model system, a pair of homologous G-domains of different stability content. The paper is just out in JPCB(2013). Quite surprisingly for our system we see that the hyperthermophilic protein show comparable and even enhanced flexibility than the mesophilic less stable variant. The more intriguing feature pops up when the global flexibility is considered. The conformational spaces sampled by the proteins were projected on a reduced network of linked kinetic separated states; and the hyperthermophiles is systematically characterised by a larger number of conformational substates! This flexibility (conformational entropy) is proposed to stabilise the protein by broadening the stability curve and consequently raising the melting temperature. I will get back on this........
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| Graphical Abstract, JPCB (2013), 117 (44), pp 13775–13785. |
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