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@ARTICLE{Dittrich:1007045,
      author       = {Dittrich, Jonas and Popara, Milana and Kubiak, Jakub and
                      Dimura, Mykola and Schepers, Bastian and Verma, Neha and
                      Schmitz, Birte and Dollinger, Peter and Kovacic, Filip and
                      Jaeger, Karl-Erich and Seidel, Claus A. M. and Peulen,
                      Thomas-Otavio and Gohlke, Holger},
      title        = {{R}esolution of {M}aximum {E}ntropy {M}ethod-{D}erived
                      {P}osterior {C}onformational {E}nsembles of a {F}lexible
                      {S}ystem {P}robed by {FRET} and {M}olecular {D}ynamics
                      {S}imulations},
      journal      = {Journal of chemical theory and computation},
      volume       = {19},
      number       = {8},
      issn         = {1549-9618},
      address      = {Washington, DC},
      reportid     = {FZJ-2023-01951},
      pages        = {2389 - 2409},
      year         = {2023},
      abstract     = {Maximum entropy methods (MEMs) determine posterior
                      distributions by combining experimental data with prior
                      information. MEMs are frequently used to reconstruct
                      conformational ensembles of molecular systems for
                      experimental information and initial molecular ensembles. We
                      performed time-resolved Förster resonance energy transfer
                      (FRET) experiments to probe the interdye distance
                      distributions of the lipase-specific foldase Lif in the apo
                      state, which likely has highly flexible, disordered, and/or
                      ordered structural elements. Distance distributions
                      estimated from ensembles of molecular dynamics (MD)
                      simulations serve as prior information, and FRET
                      experiments, analyzed within a Bayesian framework to recover
                      distance distributions, are used for optimization. We tested
                      priors obtained by MD with different force fields (FFs)
                      tailored to ordered (FF99SB, FF14SB, and FF19SB) and
                      disordered proteins (IDPSFF and FF99SBdisp). We obtained
                      five substantially different posterior ensembles. As in our
                      FRET experiments the noise is characterized by photon
                      counting statistics, for a validated dye model, MEM can
                      quantify consistencies between experiment and prior or
                      posterior ensembles. However, posterior populations of
                      conformations are uncorrelated to structural similarities
                      for individual structures selected from different prior
                      ensembles. Therefore, we assessed MEM simulating varying
                      priors in synthetic experiments with known target ensembles.
                      We found that (i) the prior and experimental information
                      must be carefully balanced for optimal posterior ensembles
                      to minimize perturbations of populations by overfitting and
                      (ii) only ensemble-integrated quantities like inter-residue
                      distance distributions or density maps can be reliably
                      obtained but not ensembles of atomistic structures. This is
                      because MEM optimizes ensembles but not individual
                      structures. This result for a highly flexible system
                      suggests that structurally varying priors calculated from
                      varying prior ensembles, e.g., generated with different FFs,
                      may serve as an ad hoc estimate for MEM reconstruction
                      robustness.},
      cin          = {IBG-4 / NIC / JSC / IBG-1 / IMET},
      ddc          = {610},
      cid          = {I:(DE-Juel1)IBG-4-20200403 / I:(DE-Juel1)NIC-20090406 /
                      I:(DE-Juel1)JSC-20090406 / I:(DE-Juel1)IBG-1-20101118 /
                      I:(DE-Juel1)IMET-20090612},
      pnm          = {2171 - Biological and environmental resources for
                      sustainable use (POF4-217) / 5111 - Domain-Specific
                      Simulation $\&$ Data Life Cycle Labs (SDLs) and Research
                      Groups (POF4-511) / Forschergruppe Gohlke $(hkf7_20200501)$
                      / Analysis of the conformational changes during activation
                      of lipase A by its foldase $(hdd16_20171101)$},
      pid          = {G:(DE-HGF)POF4-2171 / G:(DE-HGF)POF4-5111 /
                      $G:(DE-Juel1)hkf7_20200501$ / $G:(DE-Juel1)hdd16_20171101$},
      typ          = {PUB:(DE-HGF)16},
      pubmed       = {37023001},
      UT           = {WOS:000973179200001},
      doi          = {10.1021/acs.jctc.2c01090},
      url          = {https://juser.fz-juelich.de/record/1007045},
}