Improving sampling of crystallographic disorder in ensemble refinement. Issue 11 (2nd November 2021)

• Record Type: Journal Article
• Authors: Ploscariu, Nicoleta; Burnley, Tom; Gros, Piet; Pearce, Nicholas M.
• Is Part Of: Acta crystallographica. Volume 77:Issue 11(2021)
• Page Start: 1357
• Page End: 1364
• Publication Date: 2021-11-02
• Subjects: ensemble refinement -- structure refinement -- molecular dynamics -- disorder modelling; X-ray crystallography -- Periodicals; Crystallography -- Periodicals; Molecular biology -- Periodicals; Molecular structure -- Periodicals; Biomolecules -- Structure -- Periodicals; Cytology -- Periodicals; Biomolecules -- Structure; Crystallography; Cytology; Molecular biology; Molecular structure; X-ray crystallography; Periodicals; 548
• DOI: 10.1107/S2059798321010044
• Languages: English
• ISSNs: 2059-7983

Abstract

Abstract : Improvements to the ensemble refinement method are described and demonstrated. These improvements lead to more physically meaningful and interpretable macromolecular ensembles. Abstract : Ensemble refinement, the application of molecular dynamics to crystallographic refinement, explicitly models the disorder inherent in macromolecular structures. These ensemble models have been shown to produce more accurate structures than traditional single‐model structures. However, suboptimal sampling of the molecular‐dynamics simulation and modelling of crystallographic disorder has limited the utility of the method, and can lead to unphysical and strained models. Here, two improvements to the ensemble refinement method implemented within Phenix are presented: DEN restraints, which guide the local sampling of conformations and allow a more robust exploration of local conformational landscapes, and ECHT disorder models, which allow the selection of more physically meaningful and effective disorder models for parameterizing the continuous disorder components within a crystal. These improvements lead to more consistent and physically interpretable simulations of macromolecules in crystals, and allow structural heterogeneity and disorder to be systematically explored on different scales. The new approach is demonstrated on several case studies and the SARS‐CoV‐2 main protease, and demonstrates how the choice of disorder model affects the type of disorder that is sampled by the restrained molecular‐dynamics simulation.