Extending halogen-based medicinal chemistry to proteins: Iodo-Insulin as a case study
Details
Publication Year 2016-11-14, Volume 291, Issue #53, Page 27023-27041
Journal Title
Journal of Biological Chemistry
Publication Type
Journal Article
Abstract
Insulin, a protein critical for metabolic homeostasis, provides a classical model for protein design with application to human health. Recent efforts to improve its pharmaceutical formulation demonstrated that iodination of a conserved tyrosine (TyrB26) enhances key properties of a rapid-acting clinical analog. Moreover, the broad utility of halogens in medicinal chemistry has motivated use of hybrid quantum- and molecular-mechanical methods to study proteins. Here, we (i) undertook quantitative atomic-level simulations of 3-I-TyrB26-insulin to predict its structural features and (ii) tested these predictions by X-ray crystallography. Using an electrostatic model of the modified aromatic ring based on quantum chemistry, the calculations suggested that the analog - as a dimer and hexamer - exhibits subtle differences in aromatic-aromatic interactions at the dimer interface. Aromatic rings at this interface (TyrB16, PheB24, PheB25, 3-I-TyrB26 and their symmetry-related mates) adjust to enable packing of the hydrophobic iodine atoms within the core of each monomer. Strikingly, these features were observed in the crystal structure of a 3-iodo-TyrB26 insulin analog (determined as an R6 zinc hexamer). Given that residues B24-B30 detach from the core on receptor binding, the environment of 3-I-TyrB26 in a receptor complex must differ from that in the free hormone. Based on the recent structure of a "micro-receptor" complex, we predict that 3-I-TyrB26 engages the receptor via directional halogen bonding and halogen-directed hydrogen bonding: favorable electrostatic interactions exploiting, respectively, the halogen's electron-deficient sigma-hole and electronegative equatorial band. Inspired by quantum chemistry and molecular dynamics, such "halogen engineering" promises to extend principles of medicinal chemistry to proteins.
Publisher
ASBMB
WEHI Research Division(s)
Structural Biology
PubMed ID
27875310
Rights Notice
Refer to copyright notice on published article.


Creation Date: 2016-11-24 03:36:56
Last Modified: 2018-03-08 11:36:48
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