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...
| Main Authors: | , , , , , |
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| Format: | Article |
| Language: | English |
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International Union of Crystallography
2016-07-01
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| Series: | IUCrJ |
| Subjects: | |
| Online Access: | http://scripts.iucr.org/cgi-bin/paper?S2052252516008113 |
| _version_ | 1819290964927184896 |
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| author | Felix Simkovic Jens M. H. Thomas Ronan M. Keegan Martyn D. Winn Olga Mayans Daniel J. Rigden |
| author_facet | Felix Simkovic Jens M. H. Thomas Ronan M. Keegan Martyn D. Winn Olga Mayans Daniel J. Rigden |
| author_sort | Felix Simkovic |
| collection | DOAJ |
| 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 Previously encountered limitations were superseded in two key respects.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. |
| first_indexed | 2024-12-24T03:31:07Z |
| format | Article |
| id | doaj.art-3caa52adb6874381ad5968a460132805 |
| institution | Directory Open Access Journal |
| issn | 2052-2525 |
| language | English |
| last_indexed | 2024-12-24T03:31:07Z |
| publishDate | 2016-07-01 |
| publisher | International Union of Crystallography |
| record_format | Article |
| series | IUCrJ |
| spelling | doaj.art-3caa52adb6874381ad5968a4601328052022-12-21T17:17:12ZengInternational Union of CrystallographyIUCrJ2052-25252016-07-013425927010.1107/S2052252516008113lz5010Residue contacts predicted by evolutionary covariance extend the application of ab initio molecular replacement to larger and more challenging protein foldsFelix Simkovic0Jens M. H. Thomas1Ronan M. Keegan2Martyn D. Winn3Olga Mayans4Daniel J. Rigden5Institute of Integrative Biology, University of Liverpool, Liverpool L69 7ZB, EnglandInstitute of Integrative Biology, University of Liverpool, Liverpool L69 7ZB, EnglandResearch Complex at Harwell, STFC Rutherford Appleton Laboratory, Didcot OX11 0FA, EnglandScience and Technology Facilities Council, Daresbury Laboratory, Warrington WA4 4AD, EnglandInstitute of Integrative Biology, University of Liverpool, Liverpool L69 7ZB, EnglandInstitute of Integrative Biology, University of Liverpool, Liverpool L69 7ZB, EnglandFor 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.http://scripts.iucr.org/cgi-bin/paper?S2052252516008113molecular replacementprotein structure predictionevolutionary covariationpredicted contactsab initio modelling |
| spellingShingle | Felix Simkovic Jens M. H. Thomas Ronan M. Keegan Martyn D. Winn Olga Mayans Daniel J. Rigden Residue contacts predicted by evolutionary covariance extend the application of ab initio molecular replacement to larger and more challenging protein folds IUCrJ molecular replacement protein structure prediction evolutionary covariation predicted contacts ab initio modelling |
| 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 | molecular replacement protein structure prediction evolutionary covariation predicted contacts ab initio modelling |
| url | http://scripts.iucr.org/cgi-bin/paper?S2052252516008113 |
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