Zusammenfassung
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 ...
Zusammenfassung
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-J alpha (LOV2-J alpha) photoswitch inhibits the enzymatic activity of the kinase, whereas the LOV1-J alpha 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 J alpha-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.
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