Refinement of Highly Flexible Protein Structures using Simulation‐Guided Spectroscopy. Issue 52 (27th November 2018)

• Record Type: Journal Article
• Authors: Hays, Jennifer M.; Kieber, Marissa K.; Li, Jason Z.; Han, Ji In; Columbus, Linda; Kasson, Peter M.
• Is Part Of: Angewandte Chemie international edition. Volume 57:Issue 52(2018)
• Page Start: 17110
• Page End: 17114
• Publication Date: 2018-11-27
• Subjects: conformational ensembles -- EPR spectroscopy -- molecular dynamics -- mutual information -- protein structures; Chemistry -- Periodicals; 540
• DOI: 10.1002/anie.201810462
• Languages: English
• ISSNs: 1433-7851

Abstract

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. Abstract : Molecular‐dynamics‐aided spectroscopy : A method for guiding spectroscopic experiment selection that permits efficient refinement of protein conformational ensembles has been developed. This method employs molecular dynamics simulation and information theory and is tested via DEER spectroscopy.