Extending Halogen-based Medicinal Chemistry to Proteins: IODO-INSULIN AS A CASE STUDY

• Published in: The Journal of biological chemistry 2016-12, Vol.291 (53), p.27023-27041
• Main Authors: El Hage, Krystel, Pandyarajan, Vijay, Phillips, Nelson B, Smith, Brian J, Menting, John G, Whittaker, Jonathan, Lawrence, Michael C, Meuwly, Markus, Weiss, Michael A
• Format: Article
• Language: English
• Subjects: Amino Acid Sequence; Biochemistry; Biochemistry, Molecular Biology; Biophysics; Chemical Sciences; Chemistry, Pharmaceutical; Crystallography, X-Ray; Halogens; Humans; Hydrogen Bonding; Hydrophobic and Hydrophilic Interactions; Insulin - analogs & derivatives; Insulin - chemistry; Insulin - genetics; Insulin - metabolism; Life Sciences; Medicinal Chemistry; Models, Molecular; or physical chemistry; Phenylalanine - chemistry; Phenylalanine - genetics; Phenylalanine - metabolism; Protein Binding; Protein Structure and Folding; Receptor, Insulin - chemistry; Receptor, Insulin - metabolism; Structural Biology; Structure-Activity Relationship; Theoretical and; Tyrosine - chemistry; Tyrosine - genetics; Tyrosine - metabolism
• ISSN: 0021-9258; 1083-351X
• DOI: 10.1074/jbc.M116.761015

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 (Tyr ) enhances key properties of a rapid-acting clinical analog. Moreover, the broad utility of halogens in medicinal chemistry has motivated the use of hybrid quantum- and molecular-mechanical methods to study proteins. Here, we (i) undertook quantitative atomistic simulations of 3-[iodo-Tyr ]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 (Tyr , Phe , Phe , 3-I-Tyr , and their symmetry-related mates) at this interface 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-Tyr ]insulin analog (determined as an R zinc hexamer). Given that residues B24-B30 detach from the core on receptor binding, the environment of 3-I-Tyr 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-Tyr engages the receptor via directional halogen bonding and halogen-directed hydrogen bonding as follows: favorable electrostatic interactions exploiting, respectively, the halogen's electron-deficient σ-hole and electronegative equatorial band. Inspired by quantum chemistry and molecular dynamics, such "halogen engineering" promises to extend principles of medicinal chemistry to proteins.