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Induced fit with replica exchange improves protein complex structure prediction
Open accessPublished version of a preprint
Abstract
Despite the progress in prediction of protein complexes over the last decade, recent blind protein complex structure prediction challenges revealed limited success rates (less than 20% models with DockQ score > 0.4) on targets that exhibit significant conformational change upon binding. To overcome limitations in capturing backbone motions, we developed a new, aggressive sampling method that incorporates temperature replica exchange Monte Carlo (T-REMC) and conformational sampling techniques within docking protocols in Rosetta. Our method, ReplicaDock 2.0, mimics induced-fit mechanism of protein binding to sample backbone motions across putative interface residues on-the-fly, thereby recapitulating binding-partner induced conformational changes. Furthermore, ReplicaDock 2.0 clocks in at 150-500 CPU hours per target (protein-size dependent); a runtime that is significantly faster than Molecular Dynamics based approaches. For a benchmark set of 88 proteins with moderate to high flexibility (unbound-to-bound iRMSD over 1.2 Å), ReplicaDock 2.0 successfully docks 61% of moderately flexible complexes and 35% of highly flexible complexes. Additionally, we demonstrate that by biasing backbone sampling particularly towards residues comprising flexible loops or hinge domains, highly flexible targets can be predicted to under 2 Å accuracy. This indicates that additional gains are possible when mobile protein segments are known.
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Cites
Highly accurate protein structure prediction with AlphaFold
Jumper, J., Evans, R., Pritzel, A., Green, T., Figurnov, M., Ronneberger, O., Tunyasuvunakool, K., Bates, R., Žídek, A., Potapenko, A., et al. (2021) · Nature · doi:10.1038/s41586-021-03819-2 · Cited by 43,764
Understanding the Metropolis-Hastings Algorithm
Chib, S., & Greenberg, E. (1995) · The American Statistician · doi:10.1080/00031305.1995.10476177 · Cited by 4,212
Protein complex prediction with AlphaFold-Multimer
Evans, R., O’Neill, M., Pritzel, A., Antropova, N., Senior, A., Green, T., Žídek, A., Bates, R., Blackwell, S., Yim, J., et al. (2021) · doi:10.1101/2021.10.04.463034 · Cited by 3,808
The ClusPro web server for protein–protein docking
Kozakov, D., Hall, D. R., Xia, B., Porter, K. A., Padhorny, D., Yueh, C., Beglov, D., & Vajda, S. (2017) · Nature Protocols · doi:10.1038/nprot.2016.169 · Cited by 3,297
ZDOCK server: interactive docking prediction of protein–protein complexes and symmetric multimers
Pierce, B. G., Wiehe, K. J., Hwang, H., Kim, B., Vreven, T., & Weng, Z. (2014) · Bioinformatics · doi:10.1093/bioinformatics/btu097 · Cited by 1,767
Gross, K. S., Brandner, D. D., Martinez, L. A., Olive, M. F., Meisel, R. L., & Mermelstein, P. G. (2016) · PLoS ONE · doi:10.1371/journal.pone.0162755 · Cited by 1,610
The Rosetta All-Atom Energy Function for Macromolecular Modeling and Design
Alford, R. F., Leaver-Fay, A., Jeliazkov, J. R., O’Meara, M. J., DiMaio, F. P., Park, H., Shapovalov, M. V., Renfrew, P. D., Mulligan, V. K., Kappel, K., et al. (2017) · Journal of Chemical Theory and Computation · doi:10.1021/acs.jctc.7b00125 · Cited by 1,532
Self-citationPIPER: An FFT‐based protein docking program with pairwise potentials
Kozakov, D., Brenke, R., Comeau, S. R., & Vajda, S. (2006) · Proteins: Structure, Function, and Bioinformatics · doi:10.1002/prot.21117 · Cited by 865
Computational Design of Self-Assembling Protein Nanomaterials with Atomic Level Accuracy
King, N. P., Sheffler, W., Sawaya, M. R., Vollmar, B. S., Sumida, J. P., André, I., Gonen, T., Yeates, T. O., & Baker, D. A. (2012) · Science · doi:10.1126/science.1219364 · Cited by 655
Accelerating Protein Docking in ZDOCK Using an Advanced 3D Convolution Library
Pierce, B. G., Hourai, Y., & Weng, Z. (2011) · PLoS ONE · doi:10.1371/journal.pone.0024657 · Cited by 645
Accurate design of co-assembling multi-component protein nanomaterials
King, N. P., Bale, J. B., Sheffler, W., McNamara, D. E., Gonen, S., Gonen, T., Yeates, T. O., & Baker, D. A. (2014) · Nature · doi:10.1038/nature13404 · Cited by 560
DockQ: A Quality Measure for Protein-Protein Docking Models
Basu, S., & Wallner, B. (2016) · PLOS ONE · doi:10.1371/journal.pone.0161879 · Cited by 460
Abrams, C. F., & Bussi, G. (2013) · Entropy · doi:10.3390/e16010163 · Cited by 441
Assessment of blind predictions of protein–protein interactions: Current status of docking methods
Mendez, R., Leplae, R., Maria, L. D., & Wodak, S. (2003) · Proteins: Structure, Function, and Bioinformatics · doi:10.1002/prot.10393 · Cited by 438
Vreven, T., Moal, I. H., Vangone, A., Pierce, B. G., Kastritis, P. L., Torchala, M., Chaleil, R., Jiménez-García, B., Bates, P. A., Fernandez-Recio, J., et al. (2015) · Journal of Molecular Biology · doi:10.1016/j.jmb.2015.07.016 · Cited by 424
Protein–Protein Docking with Backbone Flexibility
Wang, C., Bradley, P. H., & Baker, D. A. (2007) · Journal of Molecular Biology · doi:10.1016/j.jmb.2007.07.050 · Cited by 413
Selective targeting of engineered T cells using orthogonal IL-2 cytokine-receptor complexes
Sockolosky, J. T., Trotta, E., Parisi, G., Picton, L. K., Su, L., Le, A., Chhabra, A., Silveria, S. L., George, B. M., King, I. C., et al. (2018) · Science · doi:10.1126/science.aar3246 · Cited by 380
Conformational Selection or Induced Fit? A Critical Appraisal of the Kinetic Mechanism
Vogt, A. D., & Di, E. (2012) · Biochemistry · doi:10.1021/bi3006913 · Cited by 339
Plattner, N., Doerr, S., Fabritiis, G. D., & Noé, F. (2017) · Nature Chemistry · doi:10.1038/nchem.2785 · Cited by 338
Smith, C. A., & Kortemme, T. (2008) · Journal of Molecular Biology · doi:10.1016/j.jmb.2008.05.023 · Cited by 314
Benchmarking and Analysis of Protein Docking Performance in Rosetta v3.2
Chaudhury, S., Berrondo, M., Weitzner, B. D., Muthu, P., Bergman, H., & Gray, J. J. (2011) · PLoS ONE · doi:10.1371/journal.pone.0022477 · Cited by 306
Self-citationConformational selection or induced fit? 50 years of debate resolved
Changeux, J., & Edelstein, S. J. (2011) · F1000 Biology Reports · doi:10.3410/b3-19 · Cited by 281
Structural basis for the interaction of Ras with RaIGDS
Huang, L., Hofer, F., Martin, G. S., & Kim, S. (1998) · Nature Structural Biology · doi:10.1038/nsb0698-422 · Cited by 248
Improved side‐chain modeling for protein–protein docking
Wang, C., Schueler‐Furman, O., & Baker, D. A. (2005) · Protein Science · doi:10.1110/ps.041222905 · Cited by 228
Sledzieski, S., Singh, R., Cowen, L., & Berger, B. (2021) · Cell Systems · doi:10.1016/j.cels.2021.08.010 · Cited by 219
Atomic-level characterization of protein–protein association
Pan, A. C., Jacobson, D., Yatsenko, K., Sritharan, D., Weinreich, T. M., & Shaw, D. E. (2019) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.1815431116 · Cited by 206
Regulation of Hsp70 Function by HspBP1
Shomura, Y., Dragovic, Z., Chang, H.-C., Tzvetkov, N., Young, J. C., Brodsky, J. L., Guerriero, V., Hartl, F. U., & Bracher, A. (2005) · Molecular Cell · doi:10.1016/j.molcel.2004.12.023 · Cited by 191
FiberDock: Flexible induced‐fit backbone refinement in molecular docking
Mashiach, E., Nussinov, R., & Wolfson, H. J. (2009) · Proteins Structure Function and Bioinformatics · doi:10.1002/prot.22668 · Cited by 187
Efficient flexible backbone protein-protein docking for challenging targets
Marze, N. A., Roy Burman, S. S., Sheffler, W., & Gray, J. J. (2018) · Bioinformatics · doi:10.1093/bioinformatics/bty355 · Cited by 173
Self-citationChaudhury, S., & Gray, J. J. (2008) · Journal of Molecular Biology · doi:10.1016/j.jmb.2008.05.042 · Cited by 169
Self-citationSwarmDock and the Use of Normal Modes in Protein-Protein Docking
Moal, I. H., & Bates, P. A. (2010) · International Journal of Molecular Sciences · doi:10.3390/ijms11103623 · Cited by 154
Modeling protein‐protein, protein‐peptide, and protein‐oligosaccharide complexes: CAPRI 7th edition
Lensink, M. F., Nadzirin, N., Velankar, S. S., & Wodak, S. J. (2019) · Proteins Structure Function and Bioinformatics · doi:10.1002/prot.25870 · Cited by 137
Computational design of self-assembling cyclic protein homo-oligomers
Fallas, J. A., Ueda, G., Sheffler, W., Nguyen, V., McNamara, D. E., Sankaran, B., Pereira, J. H., Parmeggiani, F., Brunette, T., Cascio, D., et al. (2016) · Nature Chemistry · doi:10.1038/nchem.2673 · Cited by 134
Blind prediction of homo- and hetero-protein complexes: the CASP13-CAPRI experiment
Lensink, M. F., Brysbaert, G., Nadzirin, N., Velankar, S., Chaleil, R. A. G., Gerguri, T., Bates, P. A., Laine, E., Carbone, A., Grudinin, S., et al. (2019) · Proteins Structure Function and Bioinformatics · doi:10.1002/prot.25838 · Cited by 122
Backbone flexibility in computational protein design
Mandell, D. J., & Kortemme, T. (2009) · Current Opinion in Biotechnology · doi:10.1016/j.copbio.2009.07.006 · Cited by 106
Prediction of protein assemblies, the next frontier: The CASP14‐CAPRI experiment
Lensink, M. F., Brysbaert, G., Mauri, T., Nadzirin, N., Velankar, S. S., Chaleil, R. A. G., Clarence, T., Bates, P. A., Kong, R., Liu, B., et al. (2021) · Proteins Structure Function and Bioinformatics · doi:10.1002/prot.26222 · Cited by 106
Self-citationFlexible protein docking refinement using pose‐dependent normal mode analysis
Venkatraman, V., & Ritchie, D. W. (2012) · Proteins Structure Function and Bioinformatics · doi:10.1002/prot.24115 · Cited by 67
Schindler, C., de Vries, S. J., & Zacharias, M. (2014) · Proteins Structure Function and Bioinformatics · doi:10.1002/prot.24728 · Cited by 65
Sense and simplicity in HADDOCK scoring: Lessons from CASP‐CAPRI round 1
Vangone, A., Rodrigues, J., Xue, L. C., van Zundert, G. C. P., Geng, C., Kurkcuoglu, Z., Nellen, M., Narasimhan, S., Karaca, E., van Dijk, M., et al. (2016) · Proteins Structure Function and Bioinformatics · doi:10.1002/prot.25198 · Cited by 62
Advances to tackle backbone flexibility in protein docking
Harmalkar, A., & Gray, J. J. (2020) · Current Opinion in Structural Biology · doi:10.1016/j.sbi.2020.11.011 · Cited by 60
Self-citationBasciu, A., Malloci, G., Pietrucci, F., Bonvin, A. M. J. J., & Vargiu, A. V. (2019) · Journal of Chemical Information and Modeling · doi:10.1021/acs.jcim.8b00730 · Cited by 50
Prediction of protein–protein complexes using replica exchange with repulsive scaling
Siebenmorgen, T., Engelhard, M., & Zacharias, M. (2020) · Journal of Computational Chemistry · doi:10.1002/jcc.26187 · Cited by 50
Pushing the Backbone in Protein-Protein Docking
Kuroda, D., & Gray, J. J. (2016) · Structure · doi:10.1016/j.str.2016.06.025 · Cited by 44
Self-citationKümmel, D., Müller, J. J., Roske, Y., Henke, N., & Heinemann, U. (2006) · Journal of Molecular Biology · doi:10.1016/j.jmb.2006.06.012 · Cited by 36
Sense and Simplicity in HADDOCK Scoring: Lessons from CASP‐CAPRI (page 418)
Vangone, A., Rodrigues, J., Xue, L. C., van Zundert, G. C. P., Geng, C., Kurkcuoglu, Z., Nellen, M., Narasimhan, S., Karaca, E., van Dijk, M., et al. (2017) · Proteins Structure Function and Bioinformatics · doi:10.1002/prot.25339 · Cited by 33
Exploring biomolecular dynamics and interactions using advanced sampling methods
Luitz, M. P., Bomblies, R., Ostermeir, K., & Zacharias, M. (2015) · Journal of Physics Condensed Matter · doi:10.1088/0953-8984/27/32/323101 · Cited by 31
Zhang, Z., Schindler, C., Lange, O. F., & Zacharias, M. (2015) · PLoS ONE · doi:10.1371/journal.pone.0125941 · Cited by 28
Alford, R. F., Smolin, N., Young, H. S., Gray, J. J., & Robia, S. L. (2020) · Journal of Biological Chemistry · doi:10.1074/jbc.ra120.012948 · Cited by 22
Self-citationReplica Exchange Improves Sampling in Low-Resolution Docking Stage of RosettaDock
Zhang, Z., & Lange, O. F. (2013) · PLoS ONE · doi:10.1371/journal.pone.0072096 · Cited by 21
Monte Carlo replica-exchange based ensemble docking of protein conformations
Zhang, Z., Ehmann, U., & Zacharias, M. (2017) · Proteins Structure Function and Bioinformatics · doi:10.1002/prot.25262 · Cited by 19
Refinement of protein-protein complexes in contact map space with metadynamics simulations
Pfeiffenberger, E., & Bates, P. A. (2019) · Proteins Structure Function and Bioinformatics · doi:10.1002/prot.25612 · Cited by 15
Ostermeir, K., & Zacharias, M. (2017) · PLoS ONE · doi:10.1371/journal.pone.0172072 · Cited by 12
Varela, D., Karlin, V., & André, I. (2022) · Structure · doi:10.1016/j.str.2022.09.005 · Cited by 12
Flagged first, then by citations
1 of the 54 references couldn’t be matched to a known paper.
Research works printed but not linked: 2
- D Varela, 2021, a Memetic Algorithm Enables Global All—Atom Protein—Protein Docking With Sidechain Flexibility, bioRxiv
- NP King, 2012, Level Accuracy, Science, 828, 1171
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Chu, L., Ruffolo, J. A., Harmalkar, A., & Gray, J. J. (2024) · Protein Science · doi:10.1002/pro.4862 · Cited by 41
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Eberhart, M. E., Alexandrova, A. N., Ajmera, P., Bím, D., Chaturvedi, S. S., Vargas, S., & Wilson, T. R. (2025) · Chemical Reviews · doi:10.1021/acs.chemrev.4c00471 · Cited by 37
Naji, S. A., Sağlık, B. N., Agamennone, M., Evren, A. E., Gündoğdu-Karaburun, N., & Karaburun, A. Ç. (2023) · ACS Omega · doi:10.1021/acsomega.3c06344 · Cited by 17
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Metadata
- Authors
- Harmalkar, A., Mahajan, S. P., & Gray, J. J.
- Affiliations
- Johns Hopkins University (US)
- Corresponding author
- Gray, Jeffrey J.
- Venue
- PLOS Computational Biology
- Publisher
- Public Library of Science (PLoS)
- Published
- 2022-06-03
- Volume
- 18
- Issue
- 6
- Pages
- e1010124
- ISSN
- 1553-734X (ISSN-L)
- 1553-7358
- PMC
- PMC9200320
- OpenAlex
- W4281708617
- Cited by
- 16
- References
- 54
- Citations by year
- 2026: 1 · 2025: 8 · 2024: 3 · 2023: 4
- FWCI
- 1.22
- Type
- journal article
- Language
- en
- Update notices
- new_version (2022-06-15)
- Open access
- gold
- doi.org
- Licence
- Locations
- PLoS Computational Biology (publishedVersion, cc-by)
- bioRxiv (Cold Spring Harbor Laboratory) (acceptedVersion, cc-by)
- PubMed Central (publishedVersion, cc-by)
- PubMed (publishedVersion)
- DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
- Funders
- National Institutes of Health (R01-GM078221, R35-GM141881)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Protein Structure and Dynamics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Structural Biology › Enzyme Structure and Function
- Life Sciences › Pharmacology, Toxicology and Pharmaceutics › Drug Discovery › Computational Drug Discovery Methods
- Keywords
- protein complex structure prediction, induced fit, parallel tempering, protein-protein docking, Rosetta
- MeSH terms
- Monte Carlo Method, Protein Binding, Protein Conformation, Proteins
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