title: Exploring the multiscale signaling behavior of phototropin1 from Chlamydomonas reinhardtii using a full-residue space kinetic Monte Carlo molecular dynamics technique.
abstract: Devising analysis tools for elucidating the regulatory mechanism of complex enzymes has been a challenging task for many decades. It generally requires the determination of the structural-dynamical information of protein solvent systems far from equilibrium over multiple length and time scales, which is still difficult both theoretically and experimentally. To cope with the problem, we introduce a full-residue space multiscale simulation method based on a combination of the kinetic Monte Carlo and molecular dynamics techniques, in which the rates of the rate-determining processes are evaluated from a biomolecular forcefield on the fly during the simulation run by taking into account the full space of residues. To demonstrate its reliability and efficiency, we explore the light-induced functional behavior of the full-length phototropin1 from Chlamydomonas reinhardtii (Cr-phot1) and its various subdomains. Our results demonstrate that in the dark state the light oxygen voltage-2-Jα (LOV2-Jα) photoswitch inhibits the enzymatic activity of the kinase, whereas the LOV1-Jα photoswitch controls the dimerization with the LOV2 domain. This leads to the repulsion of the LOV1-LOV2 linker out of the interface region between both LOV domains, which results in a positively charged surface suitable for cell-membrane interaction. By contrast, in the light state, we observe that the distance between both LOV domains is increased and the LOV1-LOV2 linker forms a helix-turn-helix (HTH) motif, which enables gene control through nucleotide binding. Finally, we find that the kinase is activated through the disruption of the Jα-helix from the LOV2 domain, which is followed by a stretching of the activation loop (A-loop) and broadening of the catalytic cleft of the kinase.
authors.affiliation: Department of Chemistry and Pharmacy, Institute of Physical and Theoretical Chemistry, University of Regensburg, D-93040, Regensburg, Germany.
authors.forename: Emanuel
authors.initials: E
authors.lastname: Peter
authors.forename: Bernhard
authors.initials: B
authors.lastname: Dick
authors.forename: Ivan
authors.initials: I
authors.lastname: Stambolic
authors.forename: Stephan A
authors.initials: SA
authors.lastname: Baeurle
mesh_terms: D000255:Adenosine Triphosphate / Q000378:metabolism*; D001665:Binding Sites; D016825:Chlamydomonas reinhardtii / Q000201:enzymology*; D008027:Light; D056004:Molecular Dynamics Simulation; D009010:Monte Carlo Method; D056949:Phototropins / Q000378:metabolism*; D011485:Protein Binding; D017510:Protein Folding; D017434:Protein Structure, Tertiary; D015398:Signal Transduction
chemical_list: D056949:Phototropins; D000255:Adenosine Triphosphate
keywords: combined kinetic Monte Carlo and molecular dynamics technique; complex signal proteins; multiscale modeling method; photoenzymes; phototropin1 from Chlamydomonas reinhardtii; signal transduction dynamics