Allosteric interactions are typically considered to proceed through a series of discrete changes in bonding interactions that alter the protein conformation. Here we show that allostery can be mediated exclusively by transmitted changes in protein motions. We have characterized the negatively cooperative binding of cAMP to the dimeric catabolite activator protein (CAP) at discrete conformational states. Binding of the first cAMP to one subunit of a CAP dimer has no effect on the conformation of the other subunit. The dynamics of the system, however, are modulated in a distinct way by the sequential ligand binding process, with the first cAMP partially enhancing and the second cAMP completely quenching protein motions. As a result, the second cAMP binding incurs a pronounced conformational entropic penalty that is entirely responsible for the observed cooperativity. The results provide strong support for the existence of purely dynamics-driven allostery.
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We thank P. Loria (Yale) and P. Huskey (Rutgers) for providing us with scripts for the analysis of some of the relaxation data. This work was supported by US National Science Foundation grant MCB-0618259 to C.G.K. and by US National Institutes of Health grant GM41376 and a Howard Hughes Medical Institute investigatorship to R.H.E.