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Ruth Nussinov

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Ruth Nussinov
Alma materUniversity of Washington, Rutgers University
Known forNucleic acid structure prediction, PLoS Computational Biology, Nussinov plots, Equilibrium unfolding, Protein–protein interaction prediction, Dynamic conformations determine protein function and cell phenotype, Conformational selection and population shift, Dynamic allostery, Current Opinion in Structural Biology
Awards
Scientific career
FieldsBioinformatics, Computational structural biology, Biophysics
InstitutionsWeizmann Institute, Berkeley, Harvard, Tel Aviv University, NCI
Thesis Secondary structure analysis of nucleic acids  (1977)
Websitehttp://ccr.cancer.gov/staff/staff.asp?profileid=6892

Ruth Nussinov (Hebrew: פרופסורית רותי נוסינוב) is an Israeli-American biologist born in Rehovot who works as a professor in the Department of Human Genetics, School of Medicine at Tel Aviv University and is the senior principal scientist and principal investigator at the National Cancer Institute, National Institutes of Health.[1] Nussinov is also the editor in chief of the Current Opinion in Structural Biology and formerly of the journal PLOS Computational Biology.[2][3]

In 1978, Nussinov proposed the first dynamic programming approach for nucleic acid secondary structure prediction, this method is now known as the Nussinov algorithm.[4][5]

Her most important discovery was in the 1990s. In 1999 Nussinov published the transformational concept that all conformations preexist—even if the crystal captures only one—and that evolution harnesses their dynamic interconversion for function, dispelling the dogma that only the wild-type shape is relevant.[6][7][8][9] Nussinov suggested a vastly different scenario from the-then dogma of two, “open” and “closed" conformations proposed by Monod, Wyman, and Changeux. She proposed that there is not one folded form, nor two—as they suggested—but many different forms, and in equilibrium, the system keeps jumping between them, and that this barrier-crossing is function. The concept that she suggested is significant since it explained that rather than the ligand inducing a conformational change (as in induced fit), the ligand can select a preexisting (relatively rare, non-minimal energy) conformation in the system that may be better suited to dock it, with minor optimization. It will then bind the ligand, and the equilibrium will keep producing more of this conformation to compensate, which she suggested (also in 1999), is the allosteric effect. This foundational “conformational selection and population shift” idea as an alternative to the “induced fit” text-book model explains the mechanism of molecular recognition. The dynamic shifts among conformations explain catalysis (2000), regulation, kinase activation, and allosteric drugs actions.[9] Her concept was confirmed by innumerable experiments and is now widely established. As Nussinov and others have shown since, this paradigm helps unravel diverse processes as signaling, regulation, and aggregation in amyloid diseases, and oncogenic transformation, contributing to extraordinary advancements in understanding structure and function.[10]

Nussinov has authored over 750 scientific papers with nearing 80,000 citations in Google Scholar, and has given hundreds of invited talks.[11][12] Most recently, she pioneered the connection, on the structural and cellular levels, of cancer and neurodevelopmental disorders asking How can same-gene mutations promote both cancer and developmental disorders?.[13]

A personal scientific overview of her biography has been published in 2018 as “Autobiography of Ruth Nussinov”.[14]

Education

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Ruth Nussinov received her B.Sc in Microbiology from University of Washington in 1966, her M.Sc in biochemistry from Rutgers University in 1967.[12] After an 8-year break to have 3 children, she went back to school in 1975, and received her Ph.D. in biochemistry from Rutgers University in 1977.[14] Her thesis was titled Secondary structure analysis of nucleic acids.[12]

Career

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She was a postdoctoral fellow at the Weizmann Institute (1977-1980) and subsequently a visiting scientist at Berkeley and at Harvard. Nussinov was in the Computer Science Department of Tel Aviv University as a senior lecturer. She took a position in Tel Aviv University Medical School in 1984 as associate professor and was promoted to professor in 1990, where she is now Professor Emeritus.[12]

Her association with the NIH started in 1983, first with the National Institute of Child Health and Human Development and, since 1985, with the National Cancer Institute.[12] Nussinov is a senior principal investigator in the Cancer Innovation Laboratory since 1985. She is also an adjunct professor in the Department of Chemistry and Biochemistry at University of Maryland since 2016.[15]

She is the editor in chief of the journal Current Opinion in Structural Biology and formerly of PLOS Computational Biology.[2][3] She also served on the editorial boards of the journals Biophysical Journal, Physical Biology,[16] Proteins,[17] BMC Bioinformatics[18] and the Journal of Biological Chemistry.

Awards and fellowships

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Scientific accomplishments

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In 1978, Nussinov published a dynamic programming algorithm for RNA secondary structure prediction, which has since been the leading method.[4] It has since been taught in bioinformatics and computational biology classes in Europe and the US, it is included in books, and exploited in multiple software packages.

Besides her work on nucleic acid secondary structure prediction, Nussinov is also regarded as a pioneer in DNA sequence analysis for her work in the early 1980s seeking genome-encoded functional signals, later becoming a trend.[29][30]

In the 1990s Nussinov pioneered the role of dynamic conformational ensembles in function, with distinct conformational states and their propensities indicators of protein and cell phenotype, and of allosteric drugs actions.[6][7][8][9] She proposed that all conformations pre-exist, and the model of “conformational selection and population shift” as an alternative to “induced fit” to explain molecular recognition.[6] The concept that she introduced emphasized that all conformational states preexist, available for a range of ligands to bind, followed by re-equilibration (shift) of the ensemble. It also clarified how allosteric posttranslational modifications can work, and underscored that lipids, ions and water molecules can also act via allostery.[9] She also proposed that all dynamic proteins are allosteric,[31] the role of allostery in disease, and how allosteric drugs work at the fundamental level. The paradigm that she introduced has impacted the scientific community's views and strategies in allosteric drug design, biomolecular engineering, molecular evolution, and cell signaling. In line with Nussinov’s proposition, dynamic population shifts are now broadly recognized as the origin of allostery. It also explains the effects of allosteric, disease-related activating mutations.[32][33][34]

The new concepts that her group pioneered have changed the way biophysicists and structural biologists think about protein-ligand interactions and are now included in chemistry/biochemistry courses. The profound significance, and advance was also heralded in Science as innovating on the decades-old concepts, noting that "although textbooks have championed the induced fit mechanism for more than 50 years, data (especially NMR) unequivocally support the powerful paradigm for diverse biological processes".[35] The conformational selection/population shift mechanism is now widely established. As Nussinov and others have shown, the new paradigm helps unravel processes as diverse as signaling, catalysis, gene regulation, and aggregation in amyloid diseases, and recently, the mechanisms of activating mutations in cancer, and addressing the puzzling question of how same-gene mutations can promote both cancer and neurodevelopmental disorders.[36][13]

References

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  1. ^ "Tel Aviv University Experts Page". Retrieved July 27, 2023.
  2. ^ a b "Current Opinion in Structural Biology - Editorial Board". Retrieved July 27, 2023.
  3. ^ a b Nussinov, Ruth (2013). "How Can PLoS Computational Biology help the biological sciences?". PLOS Computational Biology. 9 (10): e1003262. Bibcode:2013PLSCB...9E3262N. doi:10.1371/journal.pcbi.1003262. ISSN 1553-7358. PMC 3789778. PMID 24098104.
  4. ^ a b Nussinov, Ruth; Pieczenik, George; Griggs, Jerrold R.; Kleitman, Daniel J. (1 July 1978). "Algorithms for Loop Matchings". SIAM Journal on Applied Mathematics. 35 (1): 68–82. doi:10.1137/0135006.
  5. ^ Nussinov, R; Jacobson, AB (Nov 1980). "Fast algorithm for predicting the secondary structure of single-stranded RNA". Proceedings of the National Academy of Sciences of the United States of America. 77 (11): 6309–6313. Bibcode:1980PNAS...77.6309N. doi:10.1073/pnas.77.11.6309. PMC 350273. PMID 6161375.
  6. ^ a b c Tsai, Chung-Jung; Kumar, Sandeep; Ma, Buyong; Nussinov, Ruth (1999). "Folding funnels, binding funnels, and protein function". Protein Science. 8 (6): 1181–1190. doi:10.1110/ps.8.6.1181. PMC 2144348. PMID 10386868.
  7. ^ a b Ma, Buyong; Kumar, Sandeep; Tsai, Chung-Jung; Nussinov, Ruth (September 1999). "Folding funnels and binding mechanisms". Protein Engineering, Design and Selection. 12 (9): 713–720. doi:10.1093/protein/12.9.713. ISSN 1741-0134. PMID 10506280.
  8. ^ a b Tsai, Chung-Jung; Ma, Buyong; Nussinov, Ruth (1999-08-31). "Folding and binding cascades: Shifts in energy landscapes". Proceedings of the National Academy of Sciences. 96 (18): 9970–9972. Bibcode:1999PNAS...96.9970T. doi:10.1073/pnas.96.18.9970. ISSN 0027-8424. PMC 33715. PMID 10468538.
  9. ^ a b c d Kumar, Sandeep; Ma, Buyong; Tsai, Chung-Jung; Sinha, Neeti; Nussinov, Ruth (2008-12-31). "Folding and binding cascades: Dynamic landscapes and population shifts". Protein Science. 9 (1): 10–19. doi:10.1110/ps.9.1.10. PMC 2144430. PMID 10739242.
  10. ^ Ma, Buyong; Kumar, Sandeep; Tsai, Chung-Jung; Hu, Zengjian; Nussinov, Ruth (April 2000). "Transition-state Ensemble in Enzyme Catalysis: Possibility, Reality, or Necessity?". Journal of Theoretical Biology. 203 (4): 383–397. Bibcode:2000JThBi.203..383M. doi:10.1006/jtbi.2000.1097. PMID 10736215.
  11. ^ "Google Scholar Author Profile". Retrieved August 19, 2024.
  12. ^ a b c d e f g h i "Ruth Nussinov - Curriculum Vitae - February 2023" (PDF). Archived from the original (PDF) on July 25, 2023. Retrieved July 27, 2023.
  13. ^ a b Nussinov, Ruth; Tsai, Chung-Jung; Jang, Hyunbum (2022-01-14). "How can same-gene mutations promote both cancer and developmental disorders?". Science Advances. 8 (2): eabm2059. Bibcode:2022SciA....8.2059N. doi:10.1126/sciadv.abm2059. ISSN 2375-2548. PMC 8759737. PMID 35030014.
  14. ^ a b Nussinov, Ruth (2021-07-01). "Autobiography of Ruth Nussinov". The Journal of Physical Chemistry B. 125 (25): 6735–6739. doi:10.1021/acs.jpcb.1c04719. ISSN 1520-6106. PMID 34192875. S2CID 235696300.
  15. ^ "University of Maryland - Department of Chemistry & Biochemistry - People Page". Retrieved July 27, 2023.
  16. ^ "Physical Biology - Editorial Board".
  17. ^ "Proteins - Editorial Board". Retrieved July 27, 2023.
  18. ^ "BMC Bioinformatics - Editorial Board". Retrieved July 27, 2023.
  19. ^ "Society Awards - Fellow of the Biophysical Society Award - Past Awardees". Retrieved July 27, 2023.
  20. ^ Fogg, Christiana N.; Kovats, Diane E. (2013-08-22). "International Society for Computational Biology Welcomes Its Newest Class of Fellows". PLOS Computational Biology. 9 (8): e1003199. Bibcode:2013PLSCB...9E3199F. doi:10.1371/journal.pcbi.1003199. ISSN 1553-7358. PMC 3749946. PMID 23990772.
  21. ^ "Report about the 11th Israeli Bioinformatics Symposium, May 2015". Retrieved July 27, 2023.
  22. ^ "Computational Molecular Medicine: A minisymposium dedicated to Ruth Nussinov". Retrieved July 27, 2023.
  23. ^ "KeyLab conference "Recent computational and experimental advances in molecular medicine". Retrieved July 27, 2023.
  24. ^ Fogg, Christiana N.; Kovats, Diane E.; Shamir, Ron (2018). "2018 ISCB accomplishments by a senior scientist award". PLOS Computational Biology. 14 (5): e1006138. Bibcode:2018PLSCB..14E6138F. doi:10.1371/journal.pcbi.1006138. PMC 5957334. PMID 29771916.
  25. ^ "APS Fellow Archive". Retrieved July 27, 2023.
  26. ^ "Ruth Nussinov Festschrift". Retrieved July 27, 2023.
  27. ^ "Dr. Ruth Nussinov to be inducted into medical and biological engineering elite". Retrieved July 27, 2023.
  28. ^ "Outstanding scientists elected to EMBO Membership". European Molecular Biology Organization (EMBO). Retrieved August 19, 2024.
  29. ^ Kruskal, Joseph B. (April 1983). "An Overview of Sequence Comparison: Time Warps, String Edits, and Macromolecules". SIAM Review. 25 (2): 201–237. doi:10.1137/1025045. ISSN 0036-1445.
  30. ^ von Heijne, Gunnar (1987). Sequence Analysis in Molecular Biology: Treasure Trove or Trivial Pursuit. Academic Press, Inc. ISBN 978-0-12-725130-1.
  31. ^ Gunasekaran, K.; Ma, Buyong; Nussinov, Ruth (2004-07-22). "Is allostery an intrinsic property of all dynamic proteins?". Proteins: Structure, Function, and Bioinformatics. 57 (3): 433–443. doi:10.1002/prot.20232. PMID 15382234. S2CID 26108392.
  32. ^ Nussinov, Ruth; Zhang, Mingzhen; Maloney, Ryan; Liu, Yonglan; Tsai, Chung-Jung; Jang, Hyunbum (September 2022). "Allostery: Allosteric Cancer Drivers and Innovative Allosteric Drugs". Journal of Molecular Biology. 434 (17): 167569. doi:10.1016/j.jmb.2022.167569. PMC 9398924. PMID 35378118.
  33. ^ Nussinov, Ruth; Jang, Hyunbum; Gursoy, Attila; Keskin, Ozlem; Gaponenko, Vadim (February 2021). "Inhibition of Nonfunctional Ras". Cell Chemical Biology. 28 (2): 121–133. doi:10.1016/j.chembiol.2020.12.012. PMC 7897307. PMID 33440168.
  34. ^ Nussinov, Ruth; Tsai, Chung-Jung; Jang, Hyunbum (December 2019). "Why Are Some Driver Mutations Rare?". Trends in Pharmacological Sciences. 40 (12): 919–929. doi:10.1016/j.tips.2019.10.003. PMID 31699406. S2CID 207938306.
  35. ^ Boehr, David D.; Wright, Peter E. (2008-06-13). "How Do Proteins Interact?". Science. 320 (5882): 1429–1430. doi:10.1126/science.1158818. ISSN 0036-8075. PMID 18556537. S2CID 206513217.
  36. ^ Nussinov, Ruth; Tsai, Chung-Jung; Jang, Hyunbum (2022-11-15). "A New View of Activating Mutations in Cancer". Cancer Research. 82 (22): 4114–4123. doi:10.1158/0008-5472.CAN-22-2125. ISSN 0008-5472. PMC 9664134. PMID 36069825.
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