Book of Abstracts: Albany 2007
June 19-23 2007
Order through Chaos: Brownian Dynamics in Protein Allostery
We explore in detail the mechanism of ?allostery without conformational change? (1) 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 on some detail.
In the case of lac, essentially half of the allosteric free energy change on DNA binding, ΔΔG = ΔG holo - ΔGapo, is contributed via the dynamic modulation of global elastic modes of motion between the two domains of the dimer (2). The effective potentials for all relative modes tighten on binding the effector.
We show how experimental data on the dynein coiled-coil from microscopy and calorimetry can be correlated using a model that captures the elastic modes of sliding, twisting and bending of the two helices (3). The calculation also indicates how the allosteric signal to bind/unbind from phosphorylation of the central domain depends on the stiffness and coupling of the two helices, making predictions for mutations that alter the length of the stalk.
The met repressor furnishes an example of another class of entropic allosteric protein: one in which the coupling between slow, global modes and fast, local ones is important to the mechanism (4). This is clear from NMR data, and emerges theoretically as a natural consequence of the mutual interpenetration of the two monomers in the dimer. 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.
References and Footnotes
Department of Physics & Astronomy and Astbury Centre for Molecular Biology