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




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

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Journal of Proteomics


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.



Structural proteomics, Mass spectrometry, Molecular dynamics simulations, Protein-ligand interaction, Hydrogen/deuterium exchange, Crosslinking/mass spectrometry, Surface modification, Conformational change, Intrinsically disordered protein, Protein folding


Makepeace, K.A.T., Brodie, N.I., Popov, K.I., Gudavicius, G., Nelson, C.J., Petrochenko, E.V., Dokholyan, N.V. & Borchers, C.H. (2020). Ligand-induced disorder-to order transitions characterized by structural proteomics and molecular dynamics simulations. Journal of Proteomics, 211, 103544.