title: Dynamic Allostery of the Catabolite Activator Protein Revealed by Interatomic Forces.
abstract: The Catabolite Activator Protein (CAP) is a showcase example for entropic allostery. For full activation and DNA binding, the homodimeric protein requires the binding of two cyclic AMP (cAMP) molecules in an anti-cooperative manner, the source of which appears to be largely of entropic nature according to previous experimental studies. We here study at atomic detail the allosteric regulation of CAP with Molecular dynamics (MD) simulations. We recover the experimentally observed entropic penalty for the second cAMP binding event with our recently developed force covariance entropy estimator and reveal allosteric communication pathways with Force Distribution Analyses (FDA). Our observations show that CAP binding results in characteristic changes in the interaction pathways connecting the two cAMP allosteric binding sites with each other, as well as with the DNA binding domains. We identified crucial relays in the mostly symmetric allosteric activation network, and suggest point mutants to test this mechanism. Our study suggests inter-residue forces, as opposed to coordinates, as a highly sensitive measure for structural adaptations that, even though minute, can very effectively propagate allosteric signals.
authors.affiliation: Heidelberg Institutes for Theoretical Studies gGmbH, Heidelberg, Germany.
authors.forename: Maxime
authors.initials: M
authors.lastname: Louet
authors.affiliation: Heidelberg Institutes for Theoretical Studies gGmbH, Heidelberg, Germany.
authors.forename: Christian
authors.initials: C
authors.lastname: Seifert
authors.affiliation: Eidgenössische Technische Hochschule Zürich, Department of Biosystem Science and Engineering, Basel, Switzerland.
authors.forename: Ulf
authors.initials: U
authors.lastname: Hensen
authors.affiliation: Heidelberg Institutes for Theoretical Studies gGmbH, Heidelberg, Germany; CAS-MPG Partner Institute and Key Laboratory for Computational Biology, Shanghai, China.
authors.forename: Frauke
authors.initials: F
authors.lastname: Gräter
mesh_terms: D000495:Allosteric Site; D002373:Cyclic AMP Receptor Protein / Q000737:chemistry* / Q000378:metabolism*; D019277:Entropy; D029968:Escherichia coli Proteins / Q000737:chemistry / Q000378:metabolism; D056004:Molecular Dynamics Simulation; D019906:Nuclear Magnetic Resonance, Biomolecular; D025341:Principal Component Analysis; D011485:Protein Binding
chemical_list: D002373:Cyclic AMP Receptor Protein; D029968:Escherichia coli Proteins