Sidechain Dynamics and Allosteric Signaling in a PDZ Domain

Entropy-driven allostery is mediated by redistribution of conformational entropy across the sidechain network, yet the dynamic basis of this process remains poorly understood. We apply LSP-MD, a method quantifying pairwise local sidechain stability, to four functional states of the PDZ3 domain spanning 500 ns of simulation in triplicate. Although LSP-MD measurements converge within 10 ns, the sidechain stabilities drift slowly on the 100-200 ns time scale. This drift cannot be attributed to individual sidechain dynamics─it is an emergent collective behavior of the sidechain network, which we term "entropy sloshing". Principal component analysis of the data separated this stochastic background from two physically distinct signals: network stabilization by the α3 helix and the effect of peptide binding. The latter represents a clear example of entropy-driven allosteric signaling propagated through the sidechain network.