Crystal Structure of the DFNKF Segment of Human Calcitonin Unveils Aromatic Interactions between Phenylalanines

Arianna Bertolani,^[a] Andrea Pizzi,^[a] Lisa Pirrie,^[a] Lara Gazzera,^[a] Giulia Morra,^[b]
Massimiliano Meli,^[b] Giorgio Colombo,^[b] Alessandro Genoni,^{[c, d]} Gabriella Cavallo,^[a]
Giancarlo Terraneo,^[a] and Pierangelo Metrangolo^{*[a, b, e]}

[a] Laboratory of Nanostructured Fluorinated Materials (NFMLab), Department of Chemistry, Materials, and Chemical Engineering “Giulio Natta”, Politecnico di Milano
Via L. Mancinelli 7, 20131 Milano (Italy)

[b] Istituto di Chimica del Riconoscimento Molecolare, CNR Via Mario Bianco 9, 20131 Milano (Italy)

[c] Laboratoire SRSMC, UMR 7565, CNRS
Vandoeuvre-lès-Nancy, 54506 (France)

[d] Laboratoire SRSMC, UMR 7565, Université de Lorraine Vandoeuvre-lès-Nancy, 54506 (France)

[e] HYBER Centre of Excellence, Department of Applied Physics Aalto University, P.O. Box 15100, 02150, Espoo (Finland)

Chem. Eur. J. 2017, 23, 2051-2058.  DOI: 10.1002/chem.201604639

Although intensively studied, the high-resolution crystal structure of the peptide DFNKF, the core-segment of human calcitonin, has never been described. Here we report how the use of iodination as a strategy to promote crystallisation and facilitate phase determination, allowed us to solve, for the first time, the single-crystal X-ray structure of a DFNKF derivative. Computational studies suggest that both the iodinated and the wild-type peptides populate very similar conformations. Furthermore, the conformer found in the solid-state structure is one of the most populated in solution, making the crystal structure a reliable model for the peptide in solution. The crystal structure of DFNKF(I) confirms the overall features of the amyloid cross-β spine and highlights how aromatic–aromatic interactions are important structural factors in the self-assembly of this peptide. A detailed analysis of such interactions is reported.