Tom McLeish, Rhoda Hawkins*, Hedvika Toncrova*
Biophysical Sciences Institute, Durham University, UK
*Department of Physics & Astronomy and Astbury Centre for Molecular Biology University of Leeds Leeds LS2 9JT, UK
We explore in detail the mechanism of “allostery without conformational change”  by the use of coarse-grained statistical mechanical models of specific examples in molecular biology. Brownian motion excites internal degrees of freedom, which may then transmit information on state of binding to substrates across large protein domains. New examples of this important effect are continually coming to light at present as NMR and other techniques reveal dynamic, as well as structural, information on protein states. Relevant to DNA-binding repressors as well as membrane signalling proteins, such “entropic allostery” may be cast into a calculation of coarse-grained statistical mechanics, giving ground-rules for the strengths of internal interactions within such proteins. Furthermore, by parameterising the models with fully-atomistic simulations, we are able to make predictions for, e.g. changes to allostery in mutants, that brute-force simulation alone would have no chance of capturing.
We treat the cases of the lac repressor , the coiled-coil dynein tubulin-binding stalk  and the met repressor  in some detail.
A similar correlation of fast and slow modes was also reported recently in the CAP dimer. We show that large and nearly-cancelling entropic and enthalpic contributions to ΔΔG provide a characteristic calorimetric signal of this case. The strange aspect of this allosteric dimer is that the two identical binding events of the effector molecule have opposite effects: the first loosens the complex, the second tightens. This behaviour emerges naturally but surprisingly from a mode-coupling model.
 A. Cooper and D.T. Dryden, “Allostery without conformational change. A plausible model.”,,Eur. Biophys. J. 11, 103–109 (1984).
 R.J. Hawkins and T.C.B. McLeish, “Coarse-Grained Model of Entropic Allostery”, Phys. Rev. Letts, 93, 098104 (2004).
 R.J. Hawkins and T.C.B. McLeish, “Dynamic allostery of protein alpha helical coiled-coils”, J. R. Soc. Interface, 3, 125-138 (2005).
 R. J. Hawkins and T. C. B. McLeish, “Coupling of Global and Local Vibrational Modes in Dynamic Allostery of Proteins”, Biophys. J., 91, 2055-2062 (2006).
 N. Popovych, S. Sun, R. H. Ebright and C. G. Kalodimos, “Dynamically driven protein allostery”, Nature Struct. Biol., 13, 831-838 (2006).
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