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J Struct Biol. 2016 Sep;195(3):294-305. doi: 10.1016/j.jsb.2016.07.012. Epub 2016 Jul 19.

Use of evolutionary information in the fitting of atomic level protein models in low resolution cryo-EM map of a protein assembly improves the accuracy of the fitting.

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National Centre for Biological Sciences, TIFR, UAS-GKVK Campus, Bellary Road, Bangalore 560065, India; Institute of Structural and Molecular Biology, Department of Biological Sciences, Birkbeck College, University of London, Malet Street, London WC1E 7HX, UK.
Molecular Biophysics Unit, Indian Institute of Science, Bangalore 560012, India; Molecular Structure and Function Program, Hospital for Sick Children, Toronto, Canada.
Molecular Biophysics Unit, Indian Institute of Science, Bangalore 560012, India.
Molecular Biophysics Unit, Indian Institute of Science, Bangalore 560012, India. Electronic address:


Protein-protein interface residues, especially those at the core of the interface, exhibit higher conservation than residues in solvent exposed regions. Here, we explore the ability of this differential conservation to evaluate fittings of atomic models in low-resolution cryo-EM maps and select models from the ensemble of solutions that are often proposed by different model fitting techniques. As a prelude, using a non-redundant and high-resolution structural dataset involving 125 permanent and 95 transient complexes, we confirm that core interface residues are conserved significantly better than nearby non-interface residues and this result is used in the cryo-EM map analysis. From the analysis of inter-component interfaces in a set of fitted models associated with low-resolution cryo-EM maps of ribosomes, chaperones and proteasomes we note that a few poorly conserved residues occur at interfaces. Interestingly a few conserved residues are not in the interface, though they are close to the interface. These observations raise the potential requirement of refitting the models in the cryo-EM maps. We show that sampling an ensemble of models and selection of models with high residue conservation at the interface and in good agreement with the density helps in improving the accuracy of the fit. This study indicates that evolutionary information can serve as an additional input to improve and validate fitting of atomic models in cryo-EM density maps.


Cryo-EM; Cryo-EM density based fitting and modeling; Evolutionary conservation; Protein-protein interface

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