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Residue contacts predicted by evolutionary covariance extend the application of ab initio molecular replacement to larger and more challenging protein folds

For many protein families, the deluge of new sequence information together with new statistical protocols now allow the accurate prediction of contacting residues from sequence information alone. This offers the possibility of more accurate ab initio (non-homology-based) structure prediction. Such m...

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Autores principales: Simkovic, Felix, Thomas, Jens M. H., Keegan, Ronan M., Winn, Martyn D., Mayans, Olga, Rigden, Daniel J.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: International Union of Crystallography 2016
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4937781/
https://www.ncbi.nlm.nih.gov/pubmed/27437113
http://dx.doi.org/10.1107/S2052252516008113
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author Simkovic, Felix
Thomas, Jens M. H.
Keegan, Ronan M.
Winn, Martyn D.
Mayans, Olga
Rigden, Daniel J.
author_facet Simkovic, Felix
Thomas, Jens M. H.
Keegan, Ronan M.
Winn, Martyn D.
Mayans, Olga
Rigden, Daniel J.
author_sort Simkovic, Felix
collection PubMed
description For many protein families, the deluge of new sequence information together with new statistical protocols now allow the accurate prediction of contacting residues from sequence information alone. This offers the possibility of more accurate ab initio (non-homology-based) structure prediction. Such models can be used in structure solution by molecular replacement (MR) where the target fold is novel or is only distantly related to known structures. Here, AMPLE, an MR pipeline that assembles search-model ensembles from ab initio structure predictions (‘decoys’), is employed to assess the value of contact-assisted ab initio models to the crystallographer. It is demonstrated that evolutionary covariance-derived residue–residue contact predictions improve the quality of ab initio models and, consequently, the success rate of MR using search models derived from them. For targets containing β-structure, decoy quality and MR performance were further improved by the use of a β-strand contact-filtering protocol. Such contact-guided decoys achieved 14 structure solutions from 21 attempted protein targets, compared with nine for simple Rosetta decoys. Previously encountered limitations were superseded in two key respects. Firstly, much larger targets of up to 221 residues in length were solved, which is far larger than the previously benchmarked threshold of 120 residues. Secondly, contact-guided decoys significantly improved success with β-sheet-rich proteins. Overall, the improved performance of contact-guided decoys suggests that MR is now applicable to a significantly wider range of protein targets than were previously tractable, and points to a direct benefit to structural biology from the recent remarkable advances in sequencing.
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spelling pubmed-49377812016-07-19 Residue contacts predicted by evolutionary covariance extend the application of ab initio molecular replacement to larger and more challenging protein folds Simkovic, Felix Thomas, Jens M. H. Keegan, Ronan M. Winn, Martyn D. Mayans, Olga Rigden, Daniel J. IUCrJ Research Papers For many protein families, the deluge of new sequence information together with new statistical protocols now allow the accurate prediction of contacting residues from sequence information alone. This offers the possibility of more accurate ab initio (non-homology-based) structure prediction. Such models can be used in structure solution by molecular replacement (MR) where the target fold is novel or is only distantly related to known structures. Here, AMPLE, an MR pipeline that assembles search-model ensembles from ab initio structure predictions (‘decoys’), is employed to assess the value of contact-assisted ab initio models to the crystallographer. It is demonstrated that evolutionary covariance-derived residue–residue contact predictions improve the quality of ab initio models and, consequently, the success rate of MR using search models derived from them. For targets containing β-structure, decoy quality and MR performance were further improved by the use of a β-strand contact-filtering protocol. Such contact-guided decoys achieved 14 structure solutions from 21 attempted protein targets, compared with nine for simple Rosetta decoys. Previously encountered limitations were superseded in two key respects. Firstly, much larger targets of up to 221 residues in length were solved, which is far larger than the previously benchmarked threshold of 120 residues. Secondly, contact-guided decoys significantly improved success with β-sheet-rich proteins. Overall, the improved performance of contact-guided decoys suggests that MR is now applicable to a significantly wider range of protein targets than were previously tractable, and points to a direct benefit to structural biology from the recent remarkable advances in sequencing. International Union of Crystallography 2016-06-15 /pmc/articles/PMC4937781/ /pubmed/27437113 http://dx.doi.org/10.1107/S2052252516008113 Text en © Felix Simkovic et al. 2016 http://creativecommons.org/licenses/by/2.0/uk/ This is an open-access article distributed under the terms of the Creative Commons Attribution Licence, which permits unrestricted use, distribution, and reproduction in any medium, provided the original authors and source are cited.
spellingShingle Research Papers
Simkovic, Felix
Thomas, Jens M. H.
Keegan, Ronan M.
Winn, Martyn D.
Mayans, Olga
Rigden, Daniel J.
Residue contacts predicted by evolutionary covariance extend the application of ab initio molecular replacement to larger and more challenging protein folds
title Residue contacts predicted by evolutionary covariance extend the application of ab initio molecular replacement to larger and more challenging protein folds
title_full Residue contacts predicted by evolutionary covariance extend the application of ab initio molecular replacement to larger and more challenging protein folds
title_fullStr Residue contacts predicted by evolutionary covariance extend the application of ab initio molecular replacement to larger and more challenging protein folds
title_full_unstemmed Residue contacts predicted by evolutionary covariance extend the application of ab initio molecular replacement to larger and more challenging protein folds
title_short Residue contacts predicted by evolutionary covariance extend the application of ab initio molecular replacement to larger and more challenging protein folds
title_sort residue contacts predicted by evolutionary covariance extend the application of ab initio molecular replacement to larger and more challenging protein folds
topic Research Papers
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4937781/
https://www.ncbi.nlm.nih.gov/pubmed/27437113
http://dx.doi.org/10.1107/S2052252516008113
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