Your browser doesn't support javascript.
loading
Resolution of Maximum Entropy Method-Derived Posterior Conformational Ensembles of a Flexible System Probed by FRET and Molecular Dynamics Simulations.
Dittrich, Jonas; Popara, Milana; Kubiak, Jakub; Dimura, Mykola; Schepers, Bastian; Verma, Neha; Schmitz, Birte; Dollinger, Peter; Kovacic, Filip; Jaeger, Karl-Erich; Seidel, Claus A M; Peulen, Thomas-Otavio; Gohlke, Holger.
Afiliación
  • Dittrich J; Institute for Pharmaceutical and Medicinal Chemistry, Heinrich Heine University Düsseldorf, 40225 Düsseldorf, Germany.
  • Popara M; Institute for Molecular Physical Chemistry, Heinrich Heine University Düsseldorf, 40225 Düsseldorf, Germany.
  • Kubiak J; Institute for Molecular Physical Chemistry, Heinrich Heine University Düsseldorf, 40225 Düsseldorf, Germany.
  • Dimura M; Institute for Molecular Physical Chemistry, Heinrich Heine University Düsseldorf, 40225 Düsseldorf, Germany.
  • Schepers B; Institute for Pharmaceutical and Medicinal Chemistry, Heinrich Heine University Düsseldorf, 40225 Düsseldorf, Germany.
  • Verma N; Institute for Pharmaceutical and Medicinal Chemistry, Heinrich Heine University Düsseldorf, 40225 Düsseldorf, Germany.
  • Schmitz B; Institute for Pharmaceutical and Medicinal Chemistry, Heinrich Heine University Düsseldorf, 40225 Düsseldorf, Germany.
  • Dollinger P; Institute of Molecular Enzyme Technology, Heinrich Heine University Düsseldorf, 40225 Düsseldorf, Germany.
  • Kovacic F; Institute of Molecular Enzyme Technology, Heinrich Heine University Düsseldorf, 40225 Düsseldorf, Germany.
  • Jaeger KE; Institute of Molecular Enzyme Technology, Heinrich Heine University Düsseldorf, 40225 Düsseldorf, Germany.
  • Seidel CAM; Institute of Bio- and Geosciences (IBG-1: Biotechnology), Forschungszentrum Jülich GmbH, 52425 Jülich, Germany.
  • Peulen TO; Institute for Molecular Physical Chemistry, Heinrich Heine University Düsseldorf, 40225 Düsseldorf, Germany.
  • Gohlke H; Department of Bioengineering and Therapeutic Sciences and Department of Pharmaceutical Chemistry and Quantitative Biosciences Institute (QBI), University of California, San Francisco, San Francisco 94143, California, United States of America.
J Chem Theory Comput ; 19(8): 2389-2409, 2023 Apr 25.
Article en En | MEDLINE | ID: mdl-37023001
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.

Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Idioma: En Revista: J Chem Theory Comput Año: 2023 Tipo del documento: Article País de afiliación: Alemania Pais de publicación: Estados Unidos

Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Idioma: En Revista: J Chem Theory Comput Año: 2023 Tipo del documento: Article País de afiliación: Alemania Pais de publicación: Estados Unidos