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 |
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Pages (from-to) | 566-578 |
Number of pages | 13 |
Journal | Structure |
Volume | 27 |
Issue number | 4 |
DOIs | |
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