Small angle X-ray scattering and cross-linking for data assisted protein structure prediction in CASP 12 with prospects for improved accuracy

Handle URI:
http://hdl.handle.net/10754/626997
Title:
Small angle X-ray scattering and cross-linking for data assisted protein structure prediction in CASP 12 with prospects for improved accuracy
Authors:
Ogorzalek, Tadeusz L.; Hura, Greg L.; Belsom, Adam; Burnett, Kathryn H.; Kryshtafovych, Andriy ( 0000-0001-5066-7178 ) ; Tainer, John A.; Rappsilber, Juri; Tsutakawa, Susan E.; Fidelis, Krzysztof ( 0000-0002-8061-412X )
Abstract:
Experimental data offers empowering constraints for structure prediction. These constraints can be used to filter equivalently scored models or more powerfully within optimization functions toward prediction. In CASP12, Small Angle X-ray Scattering (SAXS) and Cross-Linking Mass Spectrometry (CLMS) data, measured on an exemplary set of novel fold targets, were provided to the CASP community of protein structure predictors. As HT, solution-based techniques, SAXS and CLMS can efficiently measure states of the full-length sequence in its native solution conformation and assembly. However, this experimental data did not substantially improve prediction accuracy judged by fits to crystallographic models. One issue, beyond intrinsic limitations of the algorithms, was a disconnect between crystal structures and solution-based measurements. Our analyses show that many targets had substantial percentages of disordered regions (up to 40%) or were multimeric or both. Thus, solution measurements of flexibility and assembly support variations that may confound prediction algorithms trained on crystallographic data and expecting globular fully-folded monomeric proteins. Here, we consider the CLMS and SAXS data collected, the information in these solution measurements, and the challenges in incorporating them into computational prediction. As improvement opportunities were only partly realized in CASP12, we provide guidance on how data from the full-length biological unit and the solution state can better aid prediction of the folded monomer or subunit. We furthermore describe strategic integrations of solution measurements with computational prediction programs with the aim of substantially improving foundational knowledge and the accuracy of computational algorithms for biologically-relevant structure predictions for proteins in solution. This article is protected by copyright. All rights reserved.
Citation:
Ogorzalek TL, Hura GL, Belsom A, Burnett KH, Kryshtafovych A, et al. (2018) Small angle X-ray scattering and cross-linking for data assisted protein structure prediction in CASP 12 with prospects for improved accuracy. Proteins: Structure, Function, and Bioinformatics. Available: http://dx.doi.org/10.1002/prot.25452.
Publisher:
Wiley-Blackwell
Journal:
Proteins: Structure, Function, and Bioinformatics
Issue Date:
4-Jan-2018
DOI:
10.1002/prot.25452
Type:
Article
ISSN:
0887-3585
Sponsors:
For financial support, we thank NIH (PO1CA92584 to J.A.T., R01GM110387 to S.T., and R01GM100482 to KF); and KAUST for CRG3 funding to J.A.T. J.A.T. acknowledges support by a Robert A. Welch Chemistry Chair, the Cancer Prevention and Research Institute of Texas, and the University of Texas System Science and Technology Acquisition and Retention. This research used resources of the Advanced Light Source, which are DOE Office of Science User Facilities under contract no. DE-AC02-05CH11231. The SIBYLS beamline 12.3.1 is supported by the IDAT program from the DOE BER and KAUST.
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Full metadata record

DC FieldValue Language
dc.contributor.authorOgorzalek, Tadeusz L.en
dc.contributor.authorHura, Greg L.en
dc.contributor.authorBelsom, Adamen
dc.contributor.authorBurnett, Kathryn H.en
dc.contributor.authorKryshtafovych, Andriyen
dc.contributor.authorTainer, John A.en
dc.contributor.authorRappsilber, Jurien
dc.contributor.authorTsutakawa, Susan E.en
dc.contributor.authorFidelis, Krzysztofen
dc.date.accessioned2018-02-01T08:12:00Z-
dc.date.available2018-02-01T08:12:00Z-
dc.date.issued2018-01-04en
dc.identifier.citationOgorzalek TL, Hura GL, Belsom A, Burnett KH, Kryshtafovych A, et al. (2018) Small angle X-ray scattering and cross-linking for data assisted protein structure prediction in CASP 12 with prospects for improved accuracy. Proteins: Structure, Function, and Bioinformatics. Available: http://dx.doi.org/10.1002/prot.25452.en
dc.identifier.issn0887-3585en
dc.identifier.doi10.1002/prot.25452en
dc.identifier.urihttp://hdl.handle.net/10754/626997-
dc.description.abstractExperimental data offers empowering constraints for structure prediction. These constraints can be used to filter equivalently scored models or more powerfully within optimization functions toward prediction. In CASP12, Small Angle X-ray Scattering (SAXS) and Cross-Linking Mass Spectrometry (CLMS) data, measured on an exemplary set of novel fold targets, were provided to the CASP community of protein structure predictors. As HT, solution-based techniques, SAXS and CLMS can efficiently measure states of the full-length sequence in its native solution conformation and assembly. However, this experimental data did not substantially improve prediction accuracy judged by fits to crystallographic models. One issue, beyond intrinsic limitations of the algorithms, was a disconnect between crystal structures and solution-based measurements. Our analyses show that many targets had substantial percentages of disordered regions (up to 40%) or were multimeric or both. Thus, solution measurements of flexibility and assembly support variations that may confound prediction algorithms trained on crystallographic data and expecting globular fully-folded monomeric proteins. Here, we consider the CLMS and SAXS data collected, the information in these solution measurements, and the challenges in incorporating them into computational prediction. As improvement opportunities were only partly realized in CASP12, we provide guidance on how data from the full-length biological unit and the solution state can better aid prediction of the folded monomer or subunit. We furthermore describe strategic integrations of solution measurements with computational prediction programs with the aim of substantially improving foundational knowledge and the accuracy of computational algorithms for biologically-relevant structure predictions for proteins in solution. This article is protected by copyright. All rights reserved.en
dc.description.sponsorshipFor financial support, we thank NIH (PO1CA92584 to J.A.T., R01GM110387 to S.T., and R01GM100482 to KF); and KAUST for CRG3 funding to J.A.T. J.A.T. acknowledges support by a Robert A. Welch Chemistry Chair, the Cancer Prevention and Research Institute of Texas, and the University of Texas System Science and Technology Acquisition and Retention. This research used resources of the Advanced Light Source, which are DOE Office of Science User Facilities under contract no. DE-AC02-05CH11231. The SIBYLS beamline 12.3.1 is supported by the IDAT program from the DOE BER and KAUST.en
dc.publisherWiley-Blackwellen
dc.titleSmall angle X-ray scattering and cross-linking for data assisted protein structure prediction in CASP 12 with prospects for improved accuracyen
dc.typeArticleen
dc.identifier.journalProteins: Structure, Function, and Bioinformaticsen
dc.contributor.institutionMolecular Biophysics & Integrated Bioimaging; Lawrence Berkeley National Laboratory; Berkeley California 94720 USAen
dc.contributor.institutionWellcome Trust Centre for Cell Biology, Institute of Cell Biology, School of Biological Sciences; University of Edinburgh; Edinburgh EH9 3BF U.K.en
dc.contributor.institutionProtein Structure Prediction Center, Genome and Biomedical Sciences Facilities; University of California; Davis CA 95616 USAen
dc.contributor.institutionDepartment of Molecular and Cellular Oncology; The University of Texas M. D. Anderson Cancer Center; Houston Texas 77030 USAen
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