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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

1
Departments of Biomedical Engineering and Molecular Physiology, University of Virginia, Box 800886, Charlottesvile, VA, 22908, USA.
2
Department of Chemistry, University of Virginia, Charlottesville, VA, 22908, USA.
3
Science for Life Laboratory, Program in Molecular Biophysics, Uppsala University, Uppsala, 75124, Sweden.

Abstract

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

PMID:
30395378
DOI:
10.1002/anie.201810462

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