Journal
ELIFE
Volume 1, Issue -, Pages -Publisher
eLIFE SCIENCES PUBL LTD
DOI: 10.7554/eLife.00311
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Funding
- European Research Council [233229]
- National Institutes of Health [P01GM063210]
- Netherlands Organization for Scientific Research (NWO) [01.80.104.00]
- European Research Council (ERC) [233229] Funding Source: European Research Council (ERC)
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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 angstrom 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.
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