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

J Biol Chem. 2016 Dec 30;291(53):27023-27041. doi: 10.1074/jbc.M116.761015. Epub 2016 Nov 14.

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 the use of hybrid quantum- and molecular-mechanical methods to study proteins. Here, we (i) undertook quantitative atomistic simulations of 3-[iodo-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 (TyrB16, PheB24, PheB25, 3-I-TyrB26, 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-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 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.

Keywords: diabetes; diabetes mellitus; hormone; molecular dynamics; non-standard mutagenesis; quantum chemistry; quantum mechanics; weakly polar.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Amino Acid Sequence
  • Chemistry, Pharmaceutical*
  • Crystallography, X-Ray
  • Halogens
  • Humans
  • Hydrogen Bonding
  • Hydrophobic and Hydrophilic Interactions
  • Insulin / analogs & derivatives*
  • Insulin / chemistry
  • Insulin / genetics
  • Insulin / metabolism
  • Models, Molecular
  • Phenylalanine / chemistry
  • Phenylalanine / genetics
  • Phenylalanine / metabolism
  • Protein Binding
  • Receptor, Insulin / chemistry
  • Receptor, Insulin / metabolism*
  • Structure-Activity Relationship
  • Tyrosine / chemistry
  • Tyrosine / genetics
  • Tyrosine / metabolism

Substances

  • Halogens
  • Insulin
  • insulin, iodo-
  • Tyrosine
  • Phenylalanine
  • Receptor, Insulin

Associated data

  • PDB/4OGA
  • PDB/4ZXB
  • PDB/1DPH
  • PDB/1ZNJ
  • PDB/5EMS
  • PDB/1TRZ
  • PDB/1TYL
  • PDB/1TYM
  • PDB/1RWE