Allostery in Its Many Disguises: From Theory to Applications

Shoshana J. Wodak; Emanuele Paci; Nikolay V. Dokholyan; Igor N. Berezovsky; Amnon Horovitz; Jing Li; Vincent J. Hilser; Ivet Bahar; John Karanicolas; Gerhard Stock; Peter Hamm; Roland H. Stote; Jerome Eberhardt; Yassmine Chebaro; Annick Dejaegere; Marco Cecchini; Jean Pierre Changeux; Peter G. Bolhuis; Jocelyne Vreede; Pietro Faccioli; Simone Orioli; Riccardo Ravasio; Le Yan; Carolina Brito; Matthieu Wyart; Paraskevi Gkeka; Ivan Rivalta; Giulia Palermo; J. Andrew McCammon; Joanna Panecka-Hofman; Rebecca C. Wade; Antonella Di Pizio; Masha Y. Niv; Ruth Nussinov; Chung Jung Tsai; Hyunbum Jang; Dzmitry Padhorny; Dima Kozakov; Tom McLeish

doi:10.1016/j.str.2019.01.003

Allostery in Its Many Disguises: From Theory to Applications

Shoshana J. Wodak^*, Emanuele Paci, Nikolay V. Dokholyan, Igor N. Berezovsky, Amnon Horovitz, Jing Li, Vincent J. Hilser, Ivet Bahar, John Karanicolas, Gerhard Stock, Peter Hamm, Roland H. Stote, Jerome Eberhardt, Yassmine Chebaro, Annick Dejaegere, Marco Cecchini, Jean Pierre Changeux, Peter G. Bolhuis, Jocelyne Vreede, Pietro FaccioliSimone Orioli, Riccardo Ravasio, Le Yan, Carolina Brito, Matthieu Wyart, Paraskevi Gkeka, Ivan Rivalta, Giulia Palermo, J. Andrew McCammon, Joanna Panecka-Hofman, Rebecca C. Wade, Antonella Di Pizio, Masha Y. Niv, Ruth Nussinov, Chung Jung Tsai, Hyunbum Jang, Dzmitry Padhorny, Dima Kozakov, Tom McLeish

^*Corresponding author for this work

Institute of Biochemistry, Food Science and Nutrition

Research output: Contribution to journal › Review article › peer-review

204 Scopus citations

Abstract

Allosteric regulation plays an important role in many biological processes, such as signal transduction, transcriptional regulation, and metabolism. Allostery is rooted in the fundamental physical properties of macromolecular systems, but its underlying mechanisms are still poorly understood. A collection of contributions to a recent interdisciplinary CECAM (Center Européen de Calcul Atomique et Moléculaire) workshop is used here to provide an overview of the progress and remaining limitations in the understanding of the mechanistic foundations of allostery gained from computational and experimental analyses of real protein systems and model systems. The main conceptual frameworks instrumental in driving the field are discussed. We illustrate the role of these frameworks in illuminating molecular mechanisms and explaining cellular processes, and describe some of their promising practical applications in engineering molecular sensors and informing drug design efforts. A collection of contributions to a recent interdisciplinary CECAM (Center Européen de Calcul Atomique et Moléculaire) workshop offers an insightful overview of the understanding of the mechanistic foundations of allostery, gained from computational and experimental analyses of real protein systems and model systems. Various practical applications are illustrated.

Original language	American English
Pages (from-to)	566-578
Number of pages	13
Journal	Structure
Volume	27
Issue number	4
DOIs	https://doi.org/10.1016/j.str.2019.01.003
State	Published - 2 Apr 2019

Bibliographical note

Funding Information:
M.C. and J.-P.C. acknowledge funding from the European Union's Horizon 2020 Research and Innovation Program under grant agreement no. 720270 (HBP SGA1).

Funding Information:
The Centre Européen pour le Calcul Atomic et Moléculaire (CECAM) and the Swiss Industry Science Foundation (formerly the KGF) are gratefully acknowledged for support of the CECAM workshop on Computational Approaches to Investigating Allostery. M.C. and J.-P.C. acknowledge funding from the European Union's Horizon 2020 Research and Innovation Program under grant agreement no. 720270 (HBP SGA1). N.V.D. acknowledge support by the NIH grants R01GM114015, R01GM064803, and R01GM123247, and I.B. acknowledges support from grants P41GM103712 and P30DA035778. R.N. C.-J.T. and H.J. acknowledge support in whole or in part from Federal funds from the National Cancer Institute, NIH, under contract no. HHSN261200800001E. The content of this publication does not necessarily reflect the views or policies of the Department of Health and Human Services, nor does mention of trade names, commercial products, or organizations imply endorsement by the US Government. This research was supported in part by the Intramural Research Program of the NIH, National Cancer Institute, Center for Cancer Research. G.P. and J.A.McC. thank Dr. Clarisse G. Ricci, Prof. Victor S. Batista, Dr. Amendra Fernando, Prof. Martin Jinek, and Rajshekhar Basak for having contributed to their study, and the NIH (grant no. NIG GM31749) for support. A.D.P. and M.Y.N. acknowledge funding from ISF 494/16 and ISF-NSFC 2463/16 grants. P.G. acknowledges funding from the NSRF 2007–2013, the European Regional Development Fund and national resources, under the grant “Cooperation” (no. 09ΣΥN 11-675), and the Marie Curie Reintegration Grant (FP7-PEOPLE-2009-RG, no. 256533). An AACR Judah Folkman Fellowship for Cancer Research in Angiogenesis (08-40-18-COUR) is gratefully acknowledged. We thank PRACE for awarding us access to the computational facility CURIE at GENCI@CEA, France, and are grateful for support from the LinkSCEEM-2 project, funded by the European Commission under the Seventh Framework Programme (INFRA-2010-1.2.3) Virtual Research Communities, and Combination of Collaborative Project and Coordination and Support Actions (CP-CSA) under grant agreement no. RI-261600. J.P.-H. and R.C.W. acknowledge support from the Polish National Science Centre (grant no. 2016/21/D/NZ1/02806) and the BIOMS program at the Interdisciplinary Center for Scientific Computing IWR, University of Heidelberg. Support of the Klaus Tschira Foundation is also gratefully acknowledged. S.J.W. wrote the manuscript on the basis of extended abstracts contributed by all authors. E.P. N.V.D. and A.H. helped proofreading and editing. N.V.D. I.N.B. A.H. J.L. V.J.H. I.B. J.K. G.S. P.H. R.H.S. J.E. Y.C. A.D. M.C. S.O. R.R. L.Y. C.B. M.W. P.G. I.E. G.P. J.A.McC. J.P.-H. R.C.W. A.D.P. M.Y.N. R.N. C.-J.T. H.J. D.P. D.K. and T.McL. contributed extended abstract and figures. J.P.H. declares the following additional affiliations: Center of New Technologies, University of Warsaw, Poland; Molecular and Cellular Modeling Group, Heidelberg Institute for Theoretical Studies (HITS), Germany; Interdisciplinary Center for Scientific Computing (IWR), Heidelberg University, Germany.

Funding Information:
N.V.D. acknowledge support by the NIH grants R01GM114015 , R01GM064803 , and R01GM123247 , and I.B., acknowledges support from grants P41GM103712 and P30DA035778 . R.N., C.-J.T., and H.J. acknowledge support in whole or in part from Federal funds from the National Cancer Institute , NIH, under contract no. HHSN261200800001E. The content of this publication does not necessarily reflect the views or policies of the Department of Health and Human Services, nor does mention of trade names, commercial products, or organizations imply endorsement by the US Government. This research was supported in part by the Intramural Research Program of the NIH, National Cancer Institute, Center for Cancer Research . G.P. and J.A.McC. thank Dr. Clarisse G. Ricci, Prof. Victor S. Batista, Dr. Amendra Fernando, Prof. Martin Jinek, and Rajshekhar Basak for having contributed to their study, and the NIH (grant no. NIG GM31749 ) for support. A.D.P. and M.Y.N. acknowledge funding from ISF 494/16 and ISF-NSFC 2463/16 grants. P.G. acknowledges funding from the NSRF 2007–2013, the European Regional Development Fund and national resources, under the grant “Cooperation” (no. 09ΣΥN 11-675 ), and the Marie Curie Reintegration Grant (FP7-PEOPLE-2009-RG, no. 256533 ). An AACR Judah Folkman Fellowship for Cancer Research in Angiogenesis (08-40-18-COUR) is gratefully acknowledged. We thank PRACE for awarding us access to the computational facility CURIE at GENCI@CEA , France, and are grateful for support from the LinkSCEEM-2 project, funded by the European Commission under the Seventh Framework Programme ( INFRA-2010-1.2.3 ) Virtual Research Communities, and Combination of Collaborative Project and Coordination and Support Actions (CP-CSA) under grant agreement no. RI-261600. J.P.-H., and R.C.W. acknowledge support from the Polish National Science Centre (grant no. 2016/21/D/NZ1/02806 ) and the BIOMS program at the Interdisciplinary Center for Scientific Computing IWR, University of Heidelberg . Support of the Klaus Tschira Foundation is also gratefully acknowledged.

Funding Information:
The Centre Européen pour le Calcul Atomic et Moléculaire (CECAM) and the Swiss Industry Science Foundation (formerly the KGF) are gratefully acknowledged for support of the CECAM workshop on Computational Approaches to Investigating Allostery.

Publisher Copyright:
© 2019

Keywords

Allostery
allosteric drugs
allosteric material
allosteric switches
elastic network models
energy landscape
molecular dynamics
protein conformational changes
protein function
regulation
signal transduction

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10.1016/j.str.2019.01.003

Cite this

Wodak, S. J., Paci, E., Dokholyan, N. V., Berezovsky, I. N., Horovitz, A., Li, J., Hilser, V. J., Bahar, I., Karanicolas, J., Stock, G., Hamm, P., Stote, R. H., Eberhardt, J., Chebaro, Y., Dejaegere, A., Cecchini, M., Changeux, J. P., Bolhuis, P. G., Vreede, J., ... McLeish, T. (2019). Allostery in Its Many Disguises: From Theory to Applications. Structure, 27(4), 566-578. https://doi.org/10.1016/j.str.2019.01.003

@article{086340cfb38f478099078a90209e2d2e,

title = "Allostery in Its Many Disguises: From Theory to Applications",

abstract = "Allosteric regulation plays an important role in many biological processes, such as signal transduction, transcriptional regulation, and metabolism. Allostery is rooted in the fundamental physical properties of macromolecular systems, but its underlying mechanisms are still poorly understood. A collection of contributions to a recent interdisciplinary CECAM (Center Europ{\'e}en de Calcul Atomique et Mol{\'e}culaire) workshop is used here to provide an overview of the progress and remaining limitations in the understanding of the mechanistic foundations of allostery gained from computational and experimental analyses of real protein systems and model systems. The main conceptual frameworks instrumental in driving the field are discussed. We illustrate the role of these frameworks in illuminating molecular mechanisms and explaining cellular processes, and describe some of their promising practical applications in engineering molecular sensors and informing drug design efforts. A collection of contributions to a recent interdisciplinary CECAM (Center Europ{\'e}en de Calcul Atomique et Mol{\'e}culaire) workshop offers an insightful overview of the understanding of the mechanistic foundations of allostery, gained from computational and experimental analyses of real protein systems and model systems. Various practical applications are illustrated.",

keywords = "Allostery, allosteric drugs, allosteric material, allosteric switches, elastic network models, energy landscape, molecular dynamics, protein conformational changes, protein function, regulation, signal transduction",

author = "Wodak, {Shoshana J.} and Emanuele Paci and Dokholyan, {Nikolay V.} and Berezovsky, {Igor N.} and Amnon Horovitz and Jing Li and Hilser, {Vincent J.} and Ivet Bahar and John Karanicolas and Gerhard Stock and Peter Hamm and Stote, {Roland H.} and Jerome Eberhardt and Yassmine Chebaro and Annick Dejaegere and Marco Cecchini and Changeux, {Jean Pierre} and Bolhuis, {Peter G.} and Jocelyne Vreede and Pietro Faccioli and Simone Orioli and Riccardo Ravasio and Le Yan and Carolina Brito and Matthieu Wyart and Paraskevi Gkeka and Ivan Rivalta and Giulia Palermo and McCammon, {J. Andrew} and Joanna Panecka-Hofman and Wade, {Rebecca C.} and {Di Pizio}, Antonella and Niv, {Masha Y.} and Ruth Nussinov and Tsai, {Chung Jung} and Hyunbum Jang and Dzmitry Padhorny and Dima Kozakov and Tom McLeish",

note = "Funding Information: M.C. and J.-P.C. acknowledge funding from the European Union's Horizon 2020 Research and Innovation Program under grant agreement no. 720270 (HBP SGA1). Funding Information: The Centre Europ{\'e}en pour le Calcul Atomic et Mol{\'e}culaire (CECAM) and the Swiss Industry Science Foundation (formerly the KGF) are gratefully acknowledged for support of the CECAM workshop on Computational Approaches to Investigating Allostery. M.C. and J.-P.C. acknowledge funding from the European Union's Horizon 2020 Research and Innovation Program under grant agreement no. 720270 (HBP SGA1). N.V.D. acknowledge support by the NIH grants R01GM114015, R01GM064803, and R01GM123247, and I.B. acknowledges support from grants P41GM103712 and P30DA035778. R.N. C.-J.T. and H.J. acknowledge support in whole or in part from Federal funds from the National Cancer Institute, NIH, under contract no. HHSN261200800001E. The content of this publication does not necessarily reflect the views or policies of the Department of Health and Human Services, nor does mention of trade names, commercial products, or organizations imply endorsement by the US Government. This research was supported in part by the Intramural Research Program of the NIH, National Cancer Institute, Center for Cancer Research. G.P. and J.A.McC. thank Dr. Clarisse G. Ricci, Prof. Victor S. Batista, Dr. Amendra Fernando, Prof. Martin Jinek, and Rajshekhar Basak for having contributed to their study, and the NIH (grant no. NIG GM31749) for support. A.D.P. and M.Y.N. acknowledge funding from ISF 494/16 and ISF-NSFC 2463/16 grants. P.G. acknowledges funding from the NSRF 2007–2013, the European Regional Development Fund and national resources, under the grant “Cooperation” (no. 09ΣΥN 11-675), and the Marie Curie Reintegration Grant (FP7-PEOPLE-2009-RG, no. 256533). An AACR Judah Folkman Fellowship for Cancer Research in Angiogenesis (08-40-18-COUR) is gratefully acknowledged. We thank PRACE for awarding us access to the computational facility CURIE at GENCI@CEA, France, and are grateful for support from the LinkSCEEM-2 project, funded by the European Commission under the Seventh Framework Programme (INFRA-2010-1.2.3) Virtual Research Communities, and Combination of Collaborative Project and Coordination and Support Actions (CP-CSA) under grant agreement no. RI-261600. J.P.-H. and R.C.W. acknowledge support from the Polish National Science Centre (grant no. 2016/21/D/NZ1/02806) and the BIOMS program at the Interdisciplinary Center for Scientific Computing IWR, University of Heidelberg. Support of the Klaus Tschira Foundation is also gratefully acknowledged. S.J.W. wrote the manuscript on the basis of extended abstracts contributed by all authors. E.P. N.V.D. and A.H. helped proofreading and editing. N.V.D. I.N.B. A.H. J.L. V.J.H. I.B. J.K. G.S. P.H. R.H.S. J.E. Y.C. A.D. M.C. S.O. R.R. L.Y. C.B. M.W. P.G. I.E. G.P. J.A.McC. J.P.-H. R.C.W. A.D.P. M.Y.N. R.N. C.-J.T. H.J. D.P. D.K. and T.McL. contributed extended abstract and figures. J.P.H. declares the following additional affiliations: Center of New Technologies, University of Warsaw, Poland; Molecular and Cellular Modeling Group, Heidelberg Institute for Theoretical Studies (HITS), Germany; Interdisciplinary Center for Scientific Computing (IWR), Heidelberg University, Germany. Funding Information: N.V.D. acknowledge support by the NIH grants R01GM114015 , R01GM064803 , and R01GM123247 , and I.B., acknowledges support from grants P41GM103712 and P30DA035778 . R.N., C.-J.T., and H.J. acknowledge support in whole or in part from Federal funds from the National Cancer Institute , NIH, under contract no. HHSN261200800001E. The content of this publication does not necessarily reflect the views or policies of the Department of Health and Human Services, nor does mention of trade names, commercial products, or organizations imply endorsement by the US Government. This research was supported in part by the Intramural Research Program of the NIH, National Cancer Institute, Center for Cancer Research . G.P. and J.A.McC. thank Dr. Clarisse G. Ricci, Prof. Victor S. Batista, Dr. Amendra Fernando, Prof. Martin Jinek, and Rajshekhar Basak for having contributed to their study, and the NIH (grant no. NIG GM31749 ) for support. A.D.P. and M.Y.N. acknowledge funding from ISF 494/16 and ISF-NSFC 2463/16 grants. P.G. acknowledges funding from the NSRF 2007–2013, the European Regional Development Fund and national resources, under the grant “Cooperation” (no. 09ΣΥN 11-675 ), and the Marie Curie Reintegration Grant (FP7-PEOPLE-2009-RG, no. 256533 ). An AACR Judah Folkman Fellowship for Cancer Research in Angiogenesis (08-40-18-COUR) is gratefully acknowledged. We thank PRACE for awarding us access to the computational facility CURIE at GENCI@CEA , France, and are grateful for support from the LinkSCEEM-2 project, funded by the European Commission under the Seventh Framework Programme ( INFRA-2010-1.2.3 ) Virtual Research Communities, and Combination of Collaborative Project and Coordination and Support Actions (CP-CSA) under grant agreement no. RI-261600. J.P.-H., and R.C.W. acknowledge support from the Polish National Science Centre (grant no. 2016/21/D/NZ1/02806 ) and the BIOMS program at the Interdisciplinary Center for Scientific Computing IWR, University of Heidelberg . Support of the Klaus Tschira Foundation is also gratefully acknowledged. Funding Information: The Centre Europ{\'e}en pour le Calcul Atomic et Mol{\'e}culaire (CECAM) and the Swiss Industry Science Foundation (formerly the KGF) are gratefully acknowledged for support of the CECAM workshop on Computational Approaches to Investigating Allostery. Publisher Copyright: {\textcopyright} 2019",

year = "2019",

month = apr,

day = "2",

doi = "10.1016/j.str.2019.01.003",

language = "American English",

volume = "27",

pages = "566--578",

journal = "Structure",

issn = "0969-2126",

publisher = "Cell Press",

number = "4",

}

Wodak, SJ, Paci, E, Dokholyan, NV, Berezovsky, IN, Horovitz, A, Li, J, Hilser, VJ, Bahar, I, Karanicolas, J, Stock, G, Hamm, P, Stote, RH, Eberhardt, J, Chebaro, Y, Dejaegere, A, Cecchini, M, Changeux, JP, Bolhuis, PG, Vreede, J, Faccioli, P, Orioli, S, Ravasio, R, Yan, L, Brito, C, Wyart, M, Gkeka, P, Rivalta, I, Palermo, G, McCammon, JA, Panecka-Hofman, J, Wade, RC, Di Pizio, A, Niv, MY, Nussinov, R, Tsai, CJ, Jang, H, Padhorny, D, Kozakov, D & McLeish, T 2019, 'Allostery in Its Many Disguises: From Theory to Applications', Structure, vol. 27, no. 4, pp. 566-578. https://doi.org/10.1016/j.str.2019.01.003

TY - JOUR

T1 - Allostery in Its Many Disguises

T2 - From Theory to Applications

AU - Wodak, Shoshana J.

AU - Paci, Emanuele

AU - Dokholyan, Nikolay V.

AU - Berezovsky, Igor N.

AU - Horovitz, Amnon

AU - Li, Jing

AU - Hilser, Vincent J.

AU - Bahar, Ivet

AU - Karanicolas, John

AU - Stock, Gerhard

AU - Hamm, Peter

AU - Stote, Roland H.

AU - Eberhardt, Jerome

AU - Chebaro, Yassmine

AU - Dejaegere, Annick

AU - Cecchini, Marco

AU - Changeux, Jean Pierre

AU - Bolhuis, Peter G.

AU - Vreede, Jocelyne

AU - Faccioli, Pietro

AU - Orioli, Simone

AU - Ravasio, Riccardo

AU - Yan, Le

AU - Brito, Carolina

AU - Wyart, Matthieu

AU - Gkeka, Paraskevi

AU - Rivalta, Ivan

AU - Palermo, Giulia

AU - McCammon, J. Andrew

AU - Panecka-Hofman, Joanna

AU - Wade, Rebecca C.

AU - Di Pizio, Antonella

AU - Niv, Masha Y.

AU - Nussinov, Ruth

AU - Tsai, Chung Jung

AU - Jang, Hyunbum

AU - Padhorny, Dzmitry

AU - Kozakov, Dima

AU - McLeish, Tom

N1 - Funding Information: M.C. and J.-P.C. acknowledge funding from the European Union's Horizon 2020 Research and Innovation Program under grant agreement no. 720270 (HBP SGA1). Funding Information: The Centre Européen pour le Calcul Atomic et Moléculaire (CECAM) and the Swiss Industry Science Foundation (formerly the KGF) are gratefully acknowledged for support of the CECAM workshop on Computational Approaches to Investigating Allostery. M.C. and J.-P.C. acknowledge funding from the European Union's Horizon 2020 Research and Innovation Program under grant agreement no. 720270 (HBP SGA1). N.V.D. acknowledge support by the NIH grants R01GM114015, R01GM064803, and R01GM123247, and I.B. acknowledges support from grants P41GM103712 and P30DA035778. R.N. C.-J.T. and H.J. acknowledge support in whole or in part from Federal funds from the National Cancer Institute, NIH, under contract no. HHSN261200800001E. The content of this publication does not necessarily reflect the views or policies of the Department of Health and Human Services, nor does mention of trade names, commercial products, or organizations imply endorsement by the US Government. This research was supported in part by the Intramural Research Program of the NIH, National Cancer Institute, Center for Cancer Research. G.P. and J.A.McC. thank Dr. Clarisse G. Ricci, Prof. Victor S. Batista, Dr. Amendra Fernando, Prof. Martin Jinek, and Rajshekhar Basak for having contributed to their study, and the NIH (grant no. NIG GM31749) for support. A.D.P. and M.Y.N. acknowledge funding from ISF 494/16 and ISF-NSFC 2463/16 grants. P.G. acknowledges funding from the NSRF 2007–2013, the European Regional Development Fund and national resources, under the grant “Cooperation” (no. 09ΣΥN 11-675), and the Marie Curie Reintegration Grant (FP7-PEOPLE-2009-RG, no. 256533). An AACR Judah Folkman Fellowship for Cancer Research in Angiogenesis (08-40-18-COUR) is gratefully acknowledged. We thank PRACE for awarding us access to the computational facility CURIE at GENCI@CEA, France, and are grateful for support from the LinkSCEEM-2 project, funded by the European Commission under the Seventh Framework Programme (INFRA-2010-1.2.3) Virtual Research Communities, and Combination of Collaborative Project and Coordination and Support Actions (CP-CSA) under grant agreement no. RI-261600. J.P.-H. and R.C.W. acknowledge support from the Polish National Science Centre (grant no. 2016/21/D/NZ1/02806) and the BIOMS program at the Interdisciplinary Center for Scientific Computing IWR, University of Heidelberg. Support of the Klaus Tschira Foundation is also gratefully acknowledged. S.J.W. wrote the manuscript on the basis of extended abstracts contributed by all authors. E.P. N.V.D. and A.H. helped proofreading and editing. N.V.D. I.N.B. A.H. J.L. V.J.H. I.B. J.K. G.S. P.H. R.H.S. J.E. Y.C. A.D. M.C. S.O. R.R. L.Y. C.B. M.W. P.G. I.E. G.P. J.A.McC. J.P.-H. R.C.W. A.D.P. M.Y.N. R.N. C.-J.T. H.J. D.P. D.K. and T.McL. contributed extended abstract and figures. J.P.H. declares the following additional affiliations: Center of New Technologies, University of Warsaw, Poland; Molecular and Cellular Modeling Group, Heidelberg Institute for Theoretical Studies (HITS), Germany; Interdisciplinary Center for Scientific Computing (IWR), Heidelberg University, Germany. Funding Information: N.V.D. acknowledge support by the NIH grants R01GM114015 , R01GM064803 , and R01GM123247 , and I.B., acknowledges support from grants P41GM103712 and P30DA035778 . R.N., C.-J.T., and H.J. acknowledge support in whole or in part from Federal funds from the National Cancer Institute , NIH, under contract no. HHSN261200800001E. The content of this publication does not necessarily reflect the views or policies of the Department of Health and Human Services, nor does mention of trade names, commercial products, or organizations imply endorsement by the US Government. This research was supported in part by the Intramural Research Program of the NIH, National Cancer Institute, Center for Cancer Research . G.P. and J.A.McC. thank Dr. Clarisse G. Ricci, Prof. Victor S. Batista, Dr. Amendra Fernando, Prof. Martin Jinek, and Rajshekhar Basak for having contributed to their study, and the NIH (grant no. NIG GM31749 ) for support. A.D.P. and M.Y.N. acknowledge funding from ISF 494/16 and ISF-NSFC 2463/16 grants. P.G. acknowledges funding from the NSRF 2007–2013, the European Regional Development Fund and national resources, under the grant “Cooperation” (no. 09ΣΥN 11-675 ), and the Marie Curie Reintegration Grant (FP7-PEOPLE-2009-RG, no. 256533 ). An AACR Judah Folkman Fellowship for Cancer Research in Angiogenesis (08-40-18-COUR) is gratefully acknowledged. We thank PRACE for awarding us access to the computational facility CURIE at GENCI@CEA , France, and are grateful for support from the LinkSCEEM-2 project, funded by the European Commission under the Seventh Framework Programme ( INFRA-2010-1.2.3 ) Virtual Research Communities, and Combination of Collaborative Project and Coordination and Support Actions (CP-CSA) under grant agreement no. RI-261600. J.P.-H., and R.C.W. acknowledge support from the Polish National Science Centre (grant no. 2016/21/D/NZ1/02806 ) and the BIOMS program at the Interdisciplinary Center for Scientific Computing IWR, University of Heidelberg . Support of the Klaus Tschira Foundation is also gratefully acknowledged. Funding Information: The Centre Européen pour le Calcul Atomic et Moléculaire (CECAM) and the Swiss Industry Science Foundation (formerly the KGF) are gratefully acknowledged for support of the CECAM workshop on Computational Approaches to Investigating Allostery. Publisher Copyright: © 2019

PY - 2019/4/2

Y1 - 2019/4/2

N2 - Allosteric regulation plays an important role in many biological processes, such as signal transduction, transcriptional regulation, and metabolism. Allostery is rooted in the fundamental physical properties of macromolecular systems, but its underlying mechanisms are still poorly understood. A collection of contributions to a recent interdisciplinary CECAM (Center Européen de Calcul Atomique et Moléculaire) workshop is used here to provide an overview of the progress and remaining limitations in the understanding of the mechanistic foundations of allostery gained from computational and experimental analyses of real protein systems and model systems. The main conceptual frameworks instrumental in driving the field are discussed. We illustrate the role of these frameworks in illuminating molecular mechanisms and explaining cellular processes, and describe some of their promising practical applications in engineering molecular sensors and informing drug design efforts. A collection of contributions to a recent interdisciplinary CECAM (Center Européen de Calcul Atomique et Moléculaire) workshop offers an insightful overview of the understanding of the mechanistic foundations of allostery, gained from computational and experimental analyses of real protein systems and model systems. Various practical applications are illustrated.

AB - Allosteric regulation plays an important role in many biological processes, such as signal transduction, transcriptional regulation, and metabolism. Allostery is rooted in the fundamental physical properties of macromolecular systems, but its underlying mechanisms are still poorly understood. A collection of contributions to a recent interdisciplinary CECAM (Center Européen de Calcul Atomique et Moléculaire) workshop is used here to provide an overview of the progress and remaining limitations in the understanding of the mechanistic foundations of allostery gained from computational and experimental analyses of real protein systems and model systems. The main conceptual frameworks instrumental in driving the field are discussed. We illustrate the role of these frameworks in illuminating molecular mechanisms and explaining cellular processes, and describe some of their promising practical applications in engineering molecular sensors and informing drug design efforts. A collection of contributions to a recent interdisciplinary CECAM (Center Européen de Calcul Atomique et Moléculaire) workshop offers an insightful overview of the understanding of the mechanistic foundations of allostery, gained from computational and experimental analyses of real protein systems and model systems. Various practical applications are illustrated.

KW - Allostery

KW - allosteric drugs

KW - allosteric material

KW - allosteric switches

KW - elastic network models

KW - energy landscape

KW - molecular dynamics

KW - protein conformational changes

KW - protein function

KW - regulation

KW - signal transduction

UR - http://www.scopus.com/inward/record.url?scp=85063381900&partnerID=8YFLogxK

U2 - 10.1016/j.str.2019.01.003

DO - 10.1016/j.str.2019.01.003

M3 - Review article

C2 - 30744993

AN - SCOPUS:85063381900

SN - 0969-2126

VL - 27

SP - 566

EP - 578

JO - Structure

JF - Structure

IS - 4

ER -

Allostery in Its Many Disguises: From Theory to Applications

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