Refinement of Highly Flexible Protein Structures using Simulation-Guided Spectroscopy

Angew Chem Int Ed Engl. 2018 Dec 21;57(52):17110-17114. doi: 10.1002/anie.201810462. Epub 2018 Nov 27.


Highly flexible proteins present a special challenge for structure determination because they are multi-structured yet not disordered, so their conformational ensembles are essential for understanding function. Because spectroscopic measurements of multiple conformational populations often provide sparse data, experiment selection is a limiting factor in conformational refinement. A molecular simulations- and information-theory based approach to select which experiments best refine conformational ensembles has been developed. This approach was tested on three flexible proteins. For proteins where a clear mechanistic hypothesis exists, experiments that test this hypothesis were systematically identified. When available data did not yield such mechanistic hypotheses, experiments that significantly outperform structure-guided approaches in conformational refinement were identified. This approach offers a particular advantage when refining challenging, underdetermined protein conformational ensembles.

Keywords: EPR spectroscopy; conformational ensembles; molecular dynamics; mutual information; protein structures.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Molecular Dynamics Simulation*
  • Protein Conformation
  • Proteins / chemistry*


  • Proteins