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Bomblies, R.* ; Luitz, M.P.* ; Scanu, S.* ; Madl, T. ; Zacharias, M.*

Transient helicity in intrinsically disordered Axin-1 studied by NMR spectroscopy and molecular dynamics simulations.

PLoS ONE 12:e0174337 (2017)

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Many natural proteins are, as a whole or in part, intrinsically disordered. Frequently, such intrinsically disordered regions (IDRs) undergo a transition to a defined and often helical conformation upon binding to partner molecules. The intrinsic propensity of an IDR sequence to fold into a helical conformation already in the absence of a binding partner can have a decisive influence on the binding process and affinity. Using a combination of NMR spectroscopy and molecular dynamics (MD) simulations we have investigated the tendency of regions of Axin-1, an intrinsically disordered scaffolding protein of the WNT signaling pathway, to form helices in segments interacting with binding partners. Secondary chemical shifts from NMR measurements show an increased helical population in these regions. Systematic application of MD advanced sampling approaches on peptide segments of Axin-1 reproduces the experimentally observed tendency and allows insights into the distribution of segment conformations and free energies of helix formation. The results, however, were found to dependent on the force field water model. Recent water models specifically designed for IDRs significantly reduce the predicted helical content and do not improve the agreement with experiment.

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Publication type Article: Journal article

Document type Scientific Article

Corresponding Author

Keywords Beta-catenin; Unstructured Proteins; Structural Basis; Human-diseases; Force-fields; Association; Water; Ensembles; Pathway; Regions

ISSN (print) / ISBN 1932-6203

Journal PLoS ONE

Quellenangaben Volume: 12, Issue: 3, Article Number: e0174337

Publisher Public Library of Science (PLoS)

Publishing Place Lawrence, Kan.

Non-patent literature Publications

Reviewing status Peer reviewed

Institute(s) Institute of Structural Biology (STB)