title: Long-range conformational transition of a photoswitchable allosteric protein: molecular dynamics simulation study.
abstract: A local perturbation of a protein may lead to functional changes at some distal site. An example is the PDZ2 domain of human tyrosine phosphatase 1E, which shows an allosteric transition upon binding to a peptide ligand. Recently Buchli et al. presented a time-resolved study of this transition by covalently linking an azobenzene photoswitch across the binding groove and using a femtosecond laser pulse that triggers the cis-trans photoisomerization of azobenzene. To aid the interpretation of these experiments, in this work seven microsecond runs of all-atom molecular dynamics simulations each for the wild-type PDZ2 in the ligand-bound and -free state, as well as the photoswitchable protein (PDZ2S) in the cis and trans states of the photoswitch, in explicit water were conducted. First the theoretical model is validated by recalculating the available NMR data from the simulations. By comparing the results for PDZ2 and PDZ2S, it is analyzed to what extent the photoswitch indeed mimics the free-bound transition. A detailed description of the conformational rearrangement following the cis-trans photoisomerization of PDZ2S reveals a series of photoinduced structural changes that propagate from the anchor residues of the photoswitch via intermediate secondary structure segments to the C-terminus of PDZ2S. The changes of the conformational distribution of the C-terminal region is considered as the distal response of the isolated allosteric protein.
authors.affiliation: Biomolecular Dynamics, Institute of Physics, University of Freiburg , 79104 Freiburg, Germany.
authors.forename: Sebastian
authors.initials: S
authors.lastname: Buchenberg
authors.forename: Volker
authors.initials: V
authors.lastname: Knecht
authors.forename: Reto
authors.initials: R
authors.lastname: Walser
authors.forename: Peter
authors.initials: P
authors.lastname: Hamm
authors.forename: Gerhard
authors.initials: G
authors.lastname: Stock
mesh_terms: D000494:Allosteric Regulation; D001665:Binding Sites; D006801:Humans; D056004:Molecular Dynamics Simulation; D019906:Nuclear Magnetic Resonance, Biomolecular; D055668:Photochemical Processes; D011487:Protein Conformation; D017433:Protein Structure, Secondary; D017434:Protein Structure, Tertiary; D054595:Protein Tyrosine Phosphatase, Non-Receptor Type 13 / Q000737:chemistry* / Q000528:radiation effects; D014867:Water / Q000737:chemistry
chemical_list: D014867:Water; C516742:PTPN13 protein, human; D054595:Protein Tyrosine Phosphatase, Non-Receptor Type 13