title: Detection of allosteric signal transmission by information-theoretic analysis of protein dynamics.
abstract: Allostery offers a highly specific way to modulate protein function. Therefore, understanding this mechanism is of increasing interest for protein science and drug discovery. However, allosteric signal transmission is difficult to detect experimentally and to model because it is often mediated by local structural changes propagating along multiple pathways. To address this, we developed a method to identify communication pathways by an information-theoretical analysis of molecular dynamics simulations. Signal propagation was described as information exchange through a network of correlated local motions, modeled as transitions between canonical states of protein fragments. The method was used to describe allostery in two-component regulatory systems. In particular, the transmission from the allosteric site to the signaling surface of the receiver domain NtrC was shown to be mediated by a layer of hub residues. The location of hubs preferentially connected to the allosteric site was found in close agreement with key residues experimentally identified as involved in the signal transmission. The comparison with the networks of the homologues CheY and FixJ highlighted similarities in their dynamics. In particular, we showed that a preorganized network of fragment connections between the allosteric and functional sites exists already in the inactive state of all three proteins.
authors.affiliation: Division of Mathematical Biology, Medical Research Council National Institute for Medical Research, London, UK. apandin@nimr.mrc.ac.uk
authors.forename: Alessandro
authors.initials: A
authors.lastname: Pandini
authors.forename: Arianna
authors.initials: A
authors.lastname: Fornili
authors.forename: Franca
authors.initials: F
authors.lastname: Fraternali
authors.forename: Jens
authors.initials: J
authors.lastname: Kleinjung
mesh_terms: D000494:Allosteric Regulation; D000495:Allosteric Site; D000595:Amino Acid Sequence; D001426:Bacterial Proteins / Q000737:chemistry* / Q000235:genetics; D029968:Escherichia coli Proteins / Q000737:chemistry / Q000235:genetics; D007257:Information Theory; D008565:Membrane Proteins / Q000737:chemistry / Q000235:genetics; D000072236:Methyl-Accepting Chemotaxis Proteins; D008958:Models, Molecular; D056004:Molecular Dynamics Simulation / Q000706:statistics & numerical data; D008969:Molecular Sequence Data; D051922:PII Nitrogen Regulatory Proteins / Q000737:chemistry / Q000235:genetics; D011487:Protein Conformation; D017386:Sequence Homology, Amino Acid; D015398:Signal Transduction; D012984:Software; D014157:Transcription Factors / Q000737:chemistry / Q000235:genetics
chemical_list: D001426:Bacterial Proteins; D029968:Escherichia coli Proteins; D008565:Membrane Proteins; D000072236:Methyl-Accepting Chemotaxis Proteins; D051922:PII Nitrogen Regulatory Proteins; D014157:Transcription Factors; C000607606:cheY protein, E coli; C497876:glnG protein, E coli; C069289:FixJ protein, Bacteria
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