Computational model predicts protein binding sites of a luminescent ligand equipped with guanidiniocarbonyl-pyrrole groups

Neda Rafieiolhosseini; Matthias Killa; Thorben Neumann; Niklas Tötsch; Jean-Noël Grad; Alexander Höing; Thies Dirksmeyer; Jochen Niemeyer; Christian Ottmann; Shirley K Knauer; Michael Giese; Jens Voskuhl; Daniel Hoffmann

doi:10.3762/bjoc.18.137

Computational model predicts protein binding sites of a luminescent ligand equipped with guanidiniocarbonyl-pyrrole groups

Beilstein J Org Chem. 2022 Sep 23:18:1322-1331. doi: 10.3762/bjoc.18.137. eCollection 2022.

Affiliations

¹ Bioinformatics and Computational Biophysics, Center for Medical Biotechnology (ZMB), University of Duisburg-Essen, Universitätsstraße 5, 45141 Essen, Germany.
² Faculty of Chemistry (Organic Chemistry) and CENIDE, University of Duisburg-Essen, Universitätsstraße 7, 45141 Essen, Germany.
³ Institute for Computational Physics, University of Stuttgart, Allmandring 3, 70569 Stuttgart, Germany.
⁴ Department of Molecular Biology II, Center for Medical Biotechnology (ZMB), University of Duisburg-Essen, Universitätsstraße 5, 45141 Essen, Germany.
⁵ Laboratory of Chemical Biology, Department of Biomedical Engineering and Institute for Complex Molecular Systems, Eindhoven University of Technology, PO Box 513, 5600 MB Eindhoven, Netherlands.

Abstract

The 14-3-3 protein family, one of the first discovered phosphoserine/phosphothreonine binding proteins, has attracted interest not only because of its important role in the cell regulatory processes but also due to its enormous number of interactions with other proteins. Here, we use a computational approach to predict the binding sites of the designed hybrid compound featuring aggregation-induced emission luminophores as a potential supramolecular ligand for 14-3-3ζ in the presence and absence of C-Raf peptides. Our results suggest that the area above and below the central pore of the dimeric 14-3-3ζ protein is the most probable binding site for the ligand. Moreover, we predict that the position of the ligand is sensitive to the presence of phosphorylated C-Raf peptides. With a series of experiments, we confirmed the computational prediction of two C ₂ related, dominating binding sites on 14-3-3ζ that may bind to two of the supramolecular ligand molecules.

Keywords: 14-3-3 protein; AIE luminophores; fluorescence emission; guanidiniocarbonyl-pyrrole; ligand binding.

Grants and funding

The authors wish to thank the Deutsche Forschungsgemeinschaft (CRC 1093, projects A1, A7 and A10, B4, and B5) for financial support.