An alphabet of allostery: a transferable transfer entropy contact patterns predicts allosteric-site character and conformational rewiring
Allostery is increasingly understood as the propagation of dynamic information through a protein, yet the computational descriptors of that flow are computed one structure at a time and carry no transferable, sequence-level prior. Here we build an alphabet of allostery: a dictionary of local contact words, short sequence windows anchored by three to four-residue spatial cliques, each carrying a…
Allosteric mechanisms in proteins have long been a topic of interest, with dynamic information flow being a key aspect. Previously, this flow was analyzed one structure at a time, lacking transferable, sequence-level information. To address this, a new approach has been developed - an 'alphabet of allostery'. This is essentially a dictionary of local contact words, consisting of short sequence windows anchored by three to four-residue spatial cliques, each associated with a Gaussian network model transfer entropy score. This score is computed from a non-redundant set of Protein Data Bank structures.
The alphabet comprises a staggering 131,611,766 unique words, derived from 212,860,934 clique observations. By projecting any protein's sequence and structure onto this dictionary, a per-residue allosteric track can be generated. This track includes net transfer entropy (TE), source, sink, and switch channels, all without any system-specific fitting.
When tested against the Allosteric Database, residues annotated as allosteric-sites behave as transfer entropy sinks - information receivers. The sink channel effectively distinguishes these sites from the rest of the protein, with a pooled area under the receiver operating characteristics curve (ROC-AUC) of 0.543 over 646,629 residues.
This effect, though small in magnitude, is statistically significant and remains robust against any potential word-frequency leakage.
The directional channels, source and sink, offer mechanistically informative insights. In a two-state experiment on nine canonical allosteric proteins, source residues were found to predict the largest apo-to-holo conformational rewiring, with a meta-analytic Spearman {rho} of +0.106, positive in 7 out of the 9 proteins. Conversely, sink residues were identified as the most conformationally stable positions, with a {rho} of -0.105, 8 out of 9 proteins.
This suggests that sinks mark where allosteric signal is received, while sources mark where it drives motion.
Finally, the most context-variable words from this alphabet have been selected to form a compact, hydrophobic-enriched 'switch vocabulary'. This vocabulary is proposed as a design dictionary for engineering allosteric mechanisms.
Written by urgent.news from bioRxiv's reporting — not their text. Machine-written — may contain errors; check the original before relying on it.
