Modelling dynamics in protein crystal structures by ensemble refinement
Open Access
- 18 December 2012
- journal article
- research article
- Published by eLife Sciences Publications, Ltd in eLife
- Vol. 1, e00311
- https://doi.org/10.7554/elife.00311
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 Rfree 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.Keywords
Funding Information
- European Research Council (233229)
- National Institutes of Health (P01GM063210)
- the Netherlands Organization for Scientific Research (NWO) (01.80.104.00)
- European Research Council (233229)
- National Institutes of Health (P01GM063210)
- Nederlandse Organisatie voor Wetenschappelijk Onderzoek (01.80.104.00)
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