title: Modelling dynamics in protein crystal structures by ensemble refinement.
abstract: Single-structure models derived from X-ray data do not adequately account for the inherent, functionally important dynamics of protein molecules. We generated ensembles of structures by time-averaged refinement, where local molecular vibrations were sampled by molecular-dynamics (MD) simulation whilst global disorder was partitioned into an underlying overall translation-libration-screw (TLS) model. Modeling of 20 protein datasets at 1.1-3.1 Å resolution reduced cross-validated R(free) values by 0.3-4.9%, indicating that ensemble models fit the X-ray data better than single structures. The ensembles revealed that, while most proteins display a well-ordered core, some proteins exhibit a 'molten core' likely supporting functionally important dynamics in ligand binding, enzyme activity and protomer assembly. Order-disorder changes in HIV protease indicate a mechanism of entropy compensation for ordering the catalytic residues upon ligand binding by disordering specific core residues. Thus, ensemble refinement extracts dynamical details from the X-ray data that allow a more comprehensive understanding of structure-dynamics-function relationships.DOI:http://dx.doi.org/10.7554/eLife.00311.001.
authors.affiliation: Crystal and Structural Chemistry, Bijvoet Center for Biomolecular Research, Department of Chemistry, Faculty of Science ,  Utrecht University ,  Utrecht ,  The Netherlands.
authors.forename: B Tom
authors.initials: BT
authors.lastname: Burnley
authors.forename: Pavel V
authors.initials: PV
authors.lastname: Afonine
authors.forename: Paul D
authors.initials: PD
authors.lastname: Adams
authors.forename: Piet
authors.initials: P
authors.lastname: Gros
mesh_terms: D000818:Animals; D001419:Bacteria / Q000737:chemistry; D018360:Crystallography, X-Ray; D019277:Entropy; D006801:Humans; D008024:Ligands; D015233:Models, Statistical; D056004:Molecular Dynamics Simulation; D010944:Plants / Q000737:chemistry; D011485:Protein Binding; D011487:Protein Conformation; D011506:Proteins / Q000737:chemistry*; D012984:Software; D013329:Structure-Activity Relationship; D014780:Viruses / Q000737:chemistry
chemical_list: D008024:Ligands; D011506:Proteins