Send to

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

Refinement of Highly Flexible Protein Structures using Simulation-Guided Spectroscopy.

Author information

Departments of Biomedical Engineering and Molecular Physiology, University of Virginia, Box 800886, Charlottesvile, VA, 22908, USA.
Department of Chemistry, University of Virginia, Charlottesville, VA, 22908, USA.
Science for Life Laboratory, Program in Molecular Biophysics, Uppsala University, Uppsala, 75124, Sweden.


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.


EPR spectroscopy; conformational ensembles; molecular dynamics; mutual information; protein structures


Supplemental Content

Full text links

Icon for Wiley
Loading ...
Support Center