Macromolecular modeling and design in Rosetta: recent methods and frameworks

Abstract

The Rosetta software for macromolecular modeling, docking and design is extensively used in laboratories worldwide. During two decades of development by a community of laboratories at more than 60 institutions, Rosetta has been continuously refactored and extended. Its advantages are its performance and interoperability between broad modeling capabilities. Here we review tools developed in the last 5 years, including over 80 methods. We discuss improvements to the score function, user interfaces and usability. Rosetta is available at http://www.rosettacommons.org.

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Fig. 1: Capabilities of the Rosetta macromolecular modeling suite.
Fig. 2: Main elements of Rosetta are scoring and sampling.
Fig. 3: Rosetta can successfully address diverse biological questions.
Fig. 4: User interfaces to the codebase.
Fig. 5: Main external documentation page.

Code availability.

Rosetta is licensed and distributed through https://www.rosettacommons.org. Licenses for academic, non-profit and government laboratories are free of charge; there is a license fee for industry users.

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Acknowledgements

RosettaCommons is supported by NIH R01 GM073151 to B. Kuhlman, NSF, the Packard Foundation, the Beckman Foundation, the Alfred P. Sloan Foundation and the Simons Foundation. This work was also supported by a 100,000,000 CPU-hour donation from Google Inc to P.C. and a 125,760,000 CPU-hour allocation on the Mira and Theta supercomputers through the Innovative and Novel Computational Impact on Theory and Experiment (INCITE) program to D.B., F.D., A.L.-F. and V.K.M. This research used resources of the Argonne Leadership Computing Facility, which is a DOE Office of Science user facility supported under Contract DE-AC02-06CH11357. Supported by AHA 18POST34080422 to G.K., AMED J-PRIDE JP18fm0208022h to D.K., the Biltema Foundation to B.E.C. and Boehringer Ingelheim Fonds to C.N.; computing was performed using resources of the Argonne Leadership Computing Facility at Argonne National Laboratory, which is supported by the Office of Science of the United States to P.C.; DFG KU 3510/1-1 to G.K.; DP120100561 to T.H.; DP150100383 to T.H. and K.B.P.; EMBO long-term fellowship ALTF 698-2011 to A. Stein; EPFL-Fellows H2020 Marie Sklodowska-Curie to J.B.; European Research Council Grant 310873 to O.S.-F. and N.A.; European Research Council Grant 310873 to Y. Sedan and O.M.; European Research Council Starting grant 716058 to B.E.C. and A. Scheck; FT0991709 to T.H.; Foundation of Knut and Alice Wallenberg 20160023 to L.M.; a Hertz Foundation Fellowship to R.F.A.; the Howard Hughes Medical Institute to D.B.; Hyak supercomputer system supported in part by the University of Washington eScience Institute to the D.B. and F.D. labs; Israel Science Foundation 2017717 to O.S.-F. and N.A.; Japan Society for the Promotion of Science JP17K18113 to D.K.; MCB1330760 to S.D.K.; Marie Curie International Outgoing Fellowship FP7-PEOPLE-2011-IOF 298976 to E.M.; National Science Centre, Poland, 2018/29/B/ST6/01989 to D.G.; NIAID T32AI007244 to J.A.-B.; NIAID U19 AI117905 to A.M.S.; NIEHS P42ES004699 to J.B.S.; NIGMS Ruth L Kirschstein National Research Service Award T32GM008268 to P.C.; NIGMS T32 GM007628 to B.J.B.; NIH 1R35 GM122579 to R. Das; NSF DMREF award 1728858 and DMR-0820341 to R.B.; NIH 1UH2CA203780 to S.C. and F.K.; NIH 5F32GM110899-02 to T.L.; NIH F31GM123616 to J.R.J.; NIH F32CA189246 to J.W.L.; NIH P01 U19AI117905, R01 AI113867 and UM1 Al100663 to W.S.; NIH R00 GM120388 to S.H.; NIH R01 AI143997 to N.G.S.; NIH R01 DK097376, R01 GM080403, R01 HL122010 and R01 GM099842 to J. Meiler; NIH R01 GM073960, R01 GM117968 and R01067553 to B. Kuhlman; NIH R01 GM076324 to J.B.S.; NIH R01 GM127578 and R01 GM078221 to J.J.G.; NIH R01 GM084453 to R. Dunbrack; NIH R01 GM088277 and R01 GM121487 to P. Bradley; NIH R01 GM092802, R01 GM092802, R01084433 and GM092802 to D.B.; NIH R01 GM098101, R01 GM110089 and R01 GM117189 to T.K.; NIH R01 GM099959 to J.K.; NIH R01 GM123089 to F.D.; NIH R01 GM126299 to B.G.P.; NIH R01 GM099827 to C.B.; NIH R01088277 to S.B.T.; NIH R21 AI121799 to J. Meiler; NIH R21 CA219847 and R21 GM102716 to R. Das; NIH R35 GM122517 to R. Dunbrack; NIH R35 GM125034 to N.G.S.; NIH RL1CA133832 to D.B.; NIH U19 AI117905 to J. Meiler; NIH/NCI Cancer Center support grant P30 CA006927 to J.K.; NSF 1507736 and NSF DMR 1507736 to J.J.G.; NSF 1627539, 1805510 and 1827246 to J.B.S.; NSF 1629879 to S.C.; NSF CHE 1305874, CISE 1629811 and CNS-1629811 to J. Meiler; NSF CHE 1750666 to S. Lindert; NSF DBI-1262182 and DBI-1564692 to T.K.; NSF GRF DGE-1433187 to A.R.; NSF Graduate Research Fellowships to R.F.A., K.K., B. Koepnick and S.B.T.; NSF MCB1330760 and MCB1716623 to S.D.K.; Open Philanthropy to B.C.; PhRMA Informatics Pre-Doctoral Fellowship U22879-001 to S.S.; a PhRMA Foundation Predoctoral Fellowship to D.Y.F.; RosettaCommons to L.G., A.R., F.D., S.C., A.W., M.S., C.G., K.B., R. Das, S.D.K., J. Koehler Leman and K.K.; Career Award at the Scientific Interface from Burroughs Wellcome Fund to S.E.B.; Simons Foundation to V.K.M., R.B., P.D.R. and J. Koehler Leman; a Stanford Graduate Fellowship to K.K.; a Starter Grant from the European Research Council to G.L.; Swiss National Science Foundation – NCCR Molecular Systems Engineering 51NF40-141825 to B.E.C.; Swiss National Science Foundation 310030_163139 to B.E.C.; Swiss National Science Foundation SNF 200021 160188 to L.M. and H.K.; UCSF/UCB Graduate Program in Bioengineering to X.P.; USA-Israel Binational Science Foundation 2009418 to B.R., L.Z. and N.L.; USA-Israel Binational Science Foundation 2009418 and 2015207 to O.S.-F. and N.A.; USA-Israel Binational Science Foundation 2015207 to A.K.; Washington Research Foundation Innovation Postdoctoral Fellowship to B.D.W.; XSEDE, which is supported by NSF ACI-1548562; NIH R01 GM097207 to P. Barth; and the MCB120101 XSEDE allocation to P. Barth. The authors would like to thank Jason C. Klima for his work on PyRosetta.

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Contributions

J.K.L. wrote the manuscript with help from B.D.W. All authors edited and approved the manuscript and were substantially involved in developing the methods described, either by conception of the ideas or by implementing the methods into Rosetta. The idea for this paper was conceived by R.B.

Corresponding authors

Correspondence to Julia Koehler Leman or Richard Bonneau.

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Rosetta software has been licensed to numerous non-profit and for-profit organizations. Rosetta Licensing is managed by UW CoMotion, and royalty proceeds are managed by the RosettaCommons. Under institutional participation agreements between the University of Washington, acting on behalf of the RosettaCommons, their respective institutions may be entitled to a portion of revenue received on licensing Rosetta software including programs described here. D.B., L.M., D.G., J.M., O.S.-F., J.J.G., N.G.S., S.L., J.K., R.B., T.K. and P.B. are unpaid board members of the RosettaCommons. As members of the Scientific Advisory Board of Cyrus Biotechnology, D.B. and J.J.G. are granted stock options. Y.S., I.C.K., S.M.L., B.F., K.R.K. and R.E.P. are employed at Cyrus Biotechnology with granted stock options. Cyrus Biotechnology distributes the Rosetta software. B.D.W. and S.E.B. hold equity in Lyell Immunopharma. V.K.M. is a cofounder of and shareholder in Menten Biotechnology Labs, Inc. The content of this manuscript is relevant to work performed at Lyell and Menten. J.B.S. is a cofounder and shareholder of Digestiva, Inc. and PvP Biologics Inc. D.B. is a cofounder of, shareholder in, or advisor to the following companies: ARZEDA, PvP Biologics, Cyrus Biotechnology, Cue Biopharma, Icosavax, Neoleukin Therapeutics, Lyell Immunotherapeutics, Sana Biotechnology and A-Alpha Bio.

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Leman, J.K., Weitzner, B.D., Lewis, S.M. et al. Macromolecular modeling and design in Rosetta: recent methods and frameworks. Nat Methods 17, 665–680 (2020). https://doi.org/10.1038/s41592-020-0848-2

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