Premium
Zinc Interactions with a Soluble Mutated Rat Amylin to Mimic Whole Human Amylin: An Experimental and Simulation Approach to Understand Stoichiometry, Speciation and Coordination of the Metal Complexes
Author(s) -
Magrì Antonio,
Tabbì Giovanni,
Di Natale Giuseppe,
La Mendola Diego,
Pietropaolo Adriana,
Zoroddu Maria Antonietta,
Peana Massimiliano,
Rizzarelli Enrico
Publication year - 2020
Publication title -
chemistry – a european journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.687
H-Index - 242
eISSN - 1521-3765
pISSN - 0947-6539
DOI - 10.1002/chem.202002114
Subject(s) - amylin , chemistry , zinc , stoichiometry , crystallography , amyloid (mycology) , in silico , biophysics , biochemistry , stereochemistry , islet , insulin , biology , inorganic chemistry , organic chemistry , gene , endocrinology
Islet amyloid polypeptide (IAPP) is a hormone co‐secreted with insulin and zinc from pancreatic β‐cells. To overcome the low solubility of human IAPP, we characterized zinc complexes species formed with 1) a mutated form of rat‐IAPP(1–37; R18 H) able to mimic the human IAPP, 2) the r‐IAPP(1–37) and the IAPP(1–8) fragment. Stoichiometry, speciation and coordination features of zinc(II) complexes were unveiled by ESI‐MS, potentiometry and NMR measurements combined with DFT and free‐energy simulations. Mononuclear species start to form around pH 6; Zn 2+ binds both His18 and N‐amino terminus in rat‐IAPP(1–37; R18 H). The in silico study allows us to assess not only a structured turn compact domain in r‐IAPP(1–37) and r‐IAPP(1–37; R18 H) featured by a different free energy barrier for the transition from the compact to elongated conformation upon the coordination of Zn 2+ , but also to bring into light a coordination shell further stabilized by noncovalent interactions.