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Interpreting Hydrogen-Deuterium Exchange Experiments with Molecular Simulations: Tutorials and Applications of the HDXer Ensemble Reweighting Software [Article v1.0].
Lee, Paul Suhwan; Bradshaw, Richard T; Marinelli, Fabrizio; Kihn, Kyle; Smith, Ally; Wintrode, Patrick L; Deredge, Daniel J; Faraldo-Gómez, José D; Forrest, Lucy R.
Afiliación
  • Lee PS; Computational Structural Biology Section, National Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda, MD, USA.
  • Bradshaw RT; Computational Structural Biology Section, National Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda, MD, USA.
  • Marinelli F; Theoretical Molecular Biophysics Laboratory, National Heart, Lung, and Blood Institute, National Institutes of Health, Bethesda, MD, USA.
  • Kihn K; Department of Pharmaceutical Sciences, School of Pharmacy, University of Maryland, Baltimore, MD, USA.
  • Smith A; Department of Pharmaceutical Sciences, School of Pharmacy, University of Maryland, Baltimore, MD, USA.
  • Wintrode PL; Department of Pharmaceutical Sciences, School of Pharmacy, University of Maryland, Baltimore, MD, USA.
  • Deredge DJ; Department of Pharmaceutical Sciences, School of Pharmacy, University of Maryland, Baltimore, MD, USA.
  • Faraldo-Gómez JD; Theoretical Molecular Biophysics Laboratory, National Heart, Lung, and Blood Institute, National Institutes of Health, Bethesda, MD, USA.
  • Forrest LR; Computational Structural Biology Section, National Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda, MD, USA.
Article en En | MEDLINE | ID: mdl-36644498
ABSTRACT
Hydrogen-deuterium exchange (HDX) is a comprehensive yet detailed probe of protein structure and dynamics and, coupled to mass spectrometry, has become a powerful tool for investigating an increasingly large array of systems. Computer simulations are often used to help rationalize experimental observations of exchange, but interpretations have frequently been limited to simple, subjective correlations between microscopic dynamical fluctuations and the observed macroscopic exchange behavior. With this in mind, we previously developed the HDX ensemble reweighting approach and associated software, HDXer, to aid the objective interpretation of HDX data using molecular simulations. HDXer has two main functions; first, to compute H-D exchange rates that describe each structure in a candidate ensemble of protein structures, for example from molecular simulations, and second, to objectively reweight the conformational populations present in a candidate ensemble to conform to experimental exchange data. In this article, we first describe the HDXer approach, theory, and implementation. We then guide users through a suite of tutorials that demonstrate the practical aspects of preparing experimental data, computing HDX levels from molecular simulations, and performing ensemble reweighting analyses. Finally we provide a practical discussion of the capabilities and limitations of the HDXer methods including recommendations for a user's own analyses. Overall, this article is intended to provide an up-to-date, pedagogical counterpart to the software, which is freely available at https//github.com/Lucy-Forrest-Lab/HDXer.

Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Tipo de estudio: Guideline / Qualitative_research Idioma: En Revista: Living J Comput Mol Sci Año: 2021 Tipo del documento: Article País de afiliación: Estados Unidos

Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Tipo de estudio: Guideline / Qualitative_research Idioma: En Revista: Living J Comput Mol Sci Año: 2021 Tipo del documento: Article País de afiliación: Estados Unidos
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