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July 1st, 2025
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The University of Texas Southwestern Medical Center
biophysics
biorxiv

Entropy tree networks of residue dynamics encode protein allostery

Trenfield, K.Open in Google Scholar•Lin, M. M.Open in Google Scholar

Proteins can sense signals and--in a process called allostery - transmit information to distant sites. Such information is often not encoded by a protein's average structure, but rather by its dynamics in a way that remains unclear. We show that maximum information tree networks learned from microseconds-long molecular dynamics simulations provide mechanistically-detailed maps of information transmission within proteins in a ligand- and mutation-sensitive manner. On a PDZ domain and the entire human steroid receptor family, these networks quantitatively predict functionally relevant experimental datasets spanning multiple scales, including allosteric sensitivity across a saturation mutagenesis library, calorimetric binding entropies, and phylogenetic trees. These results suggest that a sparse network of entropic couplings encodes the dynamics-to-function map; functional reprogramming and diversification by ligand binding and evolution can modify this network without changing protein structure.

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