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Protein Sci. 2010 Jul;19(7):1420-31. doi: 10.1002/pro.423.

Automated electron-density sampling reveals widespread conformational polymorphism in proteins.

Author information

1
Department of Molecular and Cell Biology, University of California, Berkeley, California 97420-3220, USA.

Abstract

Although proteins populate large structural ensembles, X-ray diffraction data are traditionally interpreted using a single model. To search for evidence of alternate conformers, we developed a program, Ringer, which systematically samples electron density around the dihedral angles of protein side chains. In a diverse set of 402 structures, Ringer identified weak, nonrandom electron-density features that suggest of the presence of hidden, lowly populated conformations for >18% of uniquely modeled residues. Although these peaks occur at electron-density levels traditionally regarded as noise, statistically significant (P < 10(-5)) enrichment of peaks at successive rotameric chi angles validates the assignment of these features as unmodeled conformations. Weak electron density corresponding to alternate rotamers also was detected in an accurate electron density map free of model bias. Ringer analysis of the high-resolution structures of free and peptide-bound calmodulin identified shifts in ensembles and connected the alternate conformations to ligand recognition. These results show that the signal in high-resolution electron density maps extends below the traditional 1 sigma cutoff, and crystalline proteins are more polymorphic than current crystallographic models. Ringer provides an objective, systematic method to identify previously undiscovered alternate conformations that can mediate protein folding and function.

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PMID:
20499387
PMCID:
PMC2974833
DOI:
10.1002/pro.423
[Indexed for MEDLINE]
Free PMC Article

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