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Assessing the utility of CASP14 models for molecular replacement
  • +7
  • Claudia Millán,
  • Ronan Keegan,
  • Joana Pereira,
  • Massimo Domenico Sammito,
  • Adam Simpkin,
  • Airlie McCoy,
  • Andrei N. Lupas,
  • Marcus Hartmann,
  • Daniel Rigden,
  • Randy Read
Claudia Millán
University of Cambridge
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Ronan Keegan
UKRI Science and Technology Facilities Council
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Joana Pereira
Universitat Basel
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Massimo Domenico Sammito
University of Cambridge
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Adam Simpkin
University of Liverpool
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Airlie McCoy
University of Cambridge
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Andrei N. Lupas
Max-Planck-Inst. for Developmental Biology
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Marcus Hartmann
Max Planck Institute for Developmental Biology
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Daniel Rigden
University of Liverpool
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Randy Read
University of Cambridge
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Abstract

The assessment of CASP models for utility in molecular replacement is a measure of their use in a valuable real-world application. In CASP7, the metric for molecular replacement assessment involved full likelihood-based molecular replacement searches; however, this restricted the assessable targets to crystal structures with only one copy of the target in the asymmetric unit, and to those where the search found the correct pose. In CASP10, full molecular replacement searches were replaced by likelihood-based rigid-body refinement of models superimposed on the target using the LGA algorithm, with the metric being the refined likelihood (LLG) score. This enabled multi-copy targets and very poor models to be evaluated, but a significant further issue remained: the requirement of diffraction data for assessment. We introduce here the relative-expected-LLG (reLLG), which is independent of diffraction data. This reLLG is also independent of any crystal form, and can be calculated regardless of the source of the target, be it X-ray, NMR or cryo-EM. We calibrate the reLLG against the LLG for targets in CASP14, showing that it is a robust measure of both model and group ranking. Like the LLG, the reLLG shows that accurate coordinate error estimates add substantial value to predicted models. We find that refinement by CASP groups can often convert an inadequate initial model into a successful MR search model. Consistent with findings from others, we show that the AlphaFold2 models are sufficiently good, and reliably so, to surpass other current model generation strategies for attempting molecular replacement phasing.

Peer review status:ACCEPTED

18 Jun 2021Submitted to PROTEINS: Structure, Function, and Bioinformatics
19 Jun 2021Submission Checks Completed
19 Jun 2021Assigned to Editor
19 Jun 2021Reviewer(s) Assigned
12 Jul 2021Review(s) Completed, Editorial Evaluation Pending
12 Jul 2021Editorial Decision: Revise Minor
20 Jul 20211st Revision Received
21 Jul 2021Submission Checks Completed
21 Jul 2021Assigned to Editor
21 Jul 2021Reviewer(s) Assigned
27 Jul 2021Review(s) Completed, Editorial Evaluation Pending
27 Jul 2021Editorial Decision: Accept