Time-resolved observation of protein allosteric communication [Biophysics and Computational Biology]
Allostery represents a fundamental mechanism of biological regulation that is mediated via long-range communication between
distant protein sites. Although little is known about the underlying dynamical process, recent time-resolved infrared spectroscopy
experiments on a photoswitchable PDZ domain (PDZ2S) have indicated that the allosteric transition occurs on multiple timescales.
Here, using extensive nonequilibrium molecular dynamics simulations, a time-dependent picture of the allosteric communication
in PDZ2S is developed. The simulations reveal that allostery amounts to the propagation of structural and dynamical changes
that are genuinely nonlinear and can occur in a nonlocal fashion. A dynamic network model is constructed that illustrates
the hierarchy and exceeding structural heterogeneity of the process. In compelling agreement with experiment, three physically
distinct phases of the time evolution are identified, describing elastic response (
≲0.1 ns), inelastic reorganization (
∼100 ns), and structural relaxation (
≳1μs). Issues such as the similarity to downhill folding as well as the interpretation of allosteric pathways are discussed.
Publisher URL: http://www.pnas.org/content/114/33/E6804.short
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