Extending halogen-based medicinal chemistry to proteins: Iodo-Insulin as a case study

El Hage, K; Pandyarajan, V; Phillips, NB; Smith, BJ; Menting, JG; Whittaker, J; Lawrence, MC; Meuwly, M; Weiss, MA

Author(s): El Hage, K; Pandyarajan, V; Phillips, NB; Smith, BJ; Menting, JG; Whittaker, J; Lawrence, MC; Meuwly, M; Weiss, MA;
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
Research Division(s): Structural Biology
PubMed ID: 27875310
Link To PubMed Central Version: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5207135/
Publisher's Version: https://doi.org/10.1074/jbc.M116.761015
Terms of Use/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