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Louet M.,Heidelberg Institutes for Theoretical Studies gGmbH | Seifert C.,Heidelberg Institutes for Theoretical Studies gGmbH | Hensen U.,ETH Zurich | Grater F.,Heidelberg Institutes for Theoretical Studies gGmbH | Grater F.,Chinese Academy of Sciences
PLoS Computational Biology | Year: 2015

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. © 2015 Louet et al.

Xia F.,Chinese Academy of Sciences | Xia F.,Heidelberg Institutes for Theoretical Studies GGmbH | Bronowska A.K.,Heidelberg Institutes for Theoretical Studies GGmbH | Cheng S.,Chinese Academy of Sciences | And 2 more authors.
Journal of Physical Chemistry B | Year: 2011

Biochemical reactions can be guided by mechanical stress. An external force has been previously shown both experimentally and theoretically to act as a catalyst for the scission of a disulfide bond in thiol/disulfide exchange reactions. How the dynamics of peptide hydrolysis, one of the most prevalent biochemical reactions, is influenced by a stretching force was investigated here using combined quantum and molecular mechanical (QM/MM) simulations together with transition path sampling. Our simulations predict mechanical force to only marginally enhance the reactivity of the rate-limiting step, the nucleophilic attack of hydroxide to the peptide moiety, and not to alter the reaction mechanism, even though the peptide bond and its electron conjugation is weakened by force. We describe a previously unidentified hydrogen bonded intermediate state, which is likely to play a role in general in base-catalyzed and analogous enzymatic reactions. Our predictions can be directly tested by single molecule stretching experiments. © 2011 American Chemical Society.

Young H.T.,Chinese Academy of Sciences | Young H.T.,University of Chinese Academy of Sciences | Edwards S.A.,Shenzhen University | Grater F.,Chinese Academy of Sciences | Grater F.,Heidelberg Institutes for Theoretical Studies gGmbH
PLoS ONE | Year: 2013

As the molecular basis of signal propagation in the cell, proteins are regulated by perturbations, such as mechanical forces or ligand binding. The question arises how fast such a signal propagates through the protein molecular scaffold. As a first step, we have investigated numerically the dynamics of force propagation through a single (Ala)40 protein following a sudden increase in the stretching forces applied to its end termini. The force propagates along the backbone into the center of the chain on the picosecond scale. Both conformational and tension dynamics are found in good agreement with a coarse-grained theory of force propagation through semiflexible polymers. The speed of force propagation of 50Å ps-1 derived from these simulations is likely to determine an upper speed limit of mechanical signal transfer in allosteric proteins or molecular machines. © 2013 Young et al.

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