Ligand-induced disorder-to-order transitions characterized by structural proteomics and molecular dynamics simulations

Karl A.T. Makepeace, Nicholas I. Brodie, Konstantin I. Popov, Geoff Gudavicius, Christopher J. Nelson, Evgeniy V. Petrotchenko, Nikolay V. Dokholyan, Christoph H. Borchers

Research output: Contribution to journalArticle

Abstract

For disordered proteins, ligand binding can be a critical event that changes their structural dynamics. The ability to characterize such changes would facilitate the development of drugs designed to stabilize disordered proteins, whose mis-folding is important for a number of pathologies, including neurodegenerative diseases such as Parkinson's and Alzheimer's diseases. In this study, we used hydrogen/deuterium exchange, differential crosslinking, differential surface modification, and molecular dynamics (MD) simulations to characterize the structural changes in disordered proteins that result from ligand binding. We show here that both an ATP-independent protein chaperone, Spy L32P, and the FK506 binding domain of a prolyl isomerase, FKBP-25 F145A/I223P, are disordered, yet exhibit structures that are distinct from chemically denatured unfolded states in solution, and that they undergo transitions to a more structured state upon ligand binding. These systems may serve as models for the characterization of ligand-induced disorder-to-order transitions in proteins using structural proteomics approaches. Significance: In this study, we used hydrogen/deuterium exchange, differential crosslinking, differential surface modification, and molecular-dynamics simulations to characterize the structural changes in disordered proteins that result from ligand binding. The protein-ligand systems studied here (the ATP-independent protein chaperone, Spy L32P, and the FK506 binding domain of a prolyl isomerase, FKBP-25 F145A/I223P) may serve as models for understanding ligand-induced disorder-to-order transitions in proteins. Additionally, the structural proteomic techniques demonstrated here are shown to be effective tools for the characterization of disorder-to-order transitions and can be used to facilitate study of other systems in which this class of structural transition can be used for modulating major pathological features of disease, such as the abnormal protein aggregation that occurs with Parkinson's disease and Alzheimer's disease.

Original languageEnglish (US)
Article number103544
JournalJournal of Proteomics
Volume211
DOIs
StatePublished - Jan 16 2020

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Molecular Dynamics Simulation
Proteomics
Molecular dynamics
Ligands
Computer simulation
Proteins
Tacrolimus Binding Proteins
Peptidylprolyl Isomerase
Deuterium
Tacrolimus
Parkinson Disease
Hydrogen
Crosslinking
Alzheimer Disease
Surface treatment
Adenosine Triphosphate
Ion exchange
Neurodegenerative diseases
Aptitude
Structural dynamics

All Science Journal Classification (ASJC) codes

  • Biophysics
  • Biochemistry

Cite this

Makepeace, K. A. T., Brodie, N. I., Popov, K. I., Gudavicius, G., Nelson, C. J., Petrotchenko, E. V., ... Borchers, C. H. (2020). Ligand-induced disorder-to-order transitions characterized by structural proteomics and molecular dynamics simulations. Journal of Proteomics, 211, [103544]. https://doi.org/10.1016/j.jprot.2019.103544
Makepeace, Karl A.T. ; Brodie, Nicholas I. ; Popov, Konstantin I. ; Gudavicius, Geoff ; Nelson, Christopher J. ; Petrotchenko, Evgeniy V. ; Dokholyan, Nikolay V. ; Borchers, Christoph H. / Ligand-induced disorder-to-order transitions characterized by structural proteomics and molecular dynamics simulations. In: Journal of Proteomics. 2020 ; Vol. 211.
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abstract = "For disordered proteins, ligand binding can be a critical event that changes their structural dynamics. The ability to characterize such changes would facilitate the development of drugs designed to stabilize disordered proteins, whose mis-folding is important for a number of pathologies, including neurodegenerative diseases such as Parkinson's and Alzheimer's diseases. In this study, we used hydrogen/deuterium exchange, differential crosslinking, differential surface modification, and molecular dynamics (MD) simulations to characterize the structural changes in disordered proteins that result from ligand binding. We show here that both an ATP-independent protein chaperone, Spy L32P, and the FK506 binding domain of a prolyl isomerase, FKBP-25 F145A/I223P, are disordered, yet exhibit structures that are distinct from chemically denatured unfolded states in solution, and that they undergo transitions to a more structured state upon ligand binding. These systems may serve as models for the characterization of ligand-induced disorder-to-order transitions in proteins using structural proteomics approaches. Significance: In this study, we used hydrogen/deuterium exchange, differential crosslinking, differential surface modification, and molecular-dynamics simulations to characterize the structural changes in disordered proteins that result from ligand binding. The protein-ligand systems studied here (the ATP-independent protein chaperone, Spy L32P, and the FK506 binding domain of a prolyl isomerase, FKBP-25 F145A/I223P) may serve as models for understanding ligand-induced disorder-to-order transitions in proteins. Additionally, the structural proteomic techniques demonstrated here are shown to be effective tools for the characterization of disorder-to-order transitions and can be used to facilitate study of other systems in which this class of structural transition can be used for modulating major pathological features of disease, such as the abnormal protein aggregation that occurs with Parkinson's disease and Alzheimer's disease.",
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Ligand-induced disorder-to-order transitions characterized by structural proteomics and molecular dynamics simulations. / Makepeace, Karl A.T.; Brodie, Nicholas I.; Popov, Konstantin I.; Gudavicius, Geoff; Nelson, Christopher J.; Petrotchenko, Evgeniy V.; Dokholyan, Nikolay V.; Borchers, Christoph H.

In: Journal of Proteomics, Vol. 211, 103544, 16.01.2020.

Research output: Contribution to journalArticle

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T1 - Ligand-induced disorder-to-order transitions characterized by structural proteomics and molecular dynamics simulations

AU - Makepeace, Karl A.T.

AU - Brodie, Nicholas I.

AU - Popov, Konstantin I.

AU - Gudavicius, Geoff

AU - Nelson, Christopher J.

AU - Petrotchenko, Evgeniy V.

AU - Dokholyan, Nikolay V.

AU - Borchers, Christoph H.

PY - 2020/1/16

Y1 - 2020/1/16

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