Journal
IUCRJ
Volume 3, Issue -, Pages 259-270Publisher
INT UNION CRYSTALLOGRAPHY
DOI: 10.1107/S2052252516008113
Keywords
molecular replacement; protein structure prediction; evolutionary covariation; predicted contacts; ab initio modelling
Funding
- BBSRC grant 'CCP4 Grant Renewal: Question-driven crystallographic data collection and advanced structure solution' [BB/L009544/1]
- BBSRC DTP PhD scholarships
- BBSRC [BB/L008777/1, BB/L009544/1] Funding Source: UKRI
- Biotechnology and Biological Sciences Research Council [1511100, BB/L009544/1, 1221779, BB/L008777/1] Funding Source: researchfish
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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 beta-structure, decoy quality and MR performance were further improved by the use of a beta-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 Previously encountered limitations were superseded in two key respects.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 beta-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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