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

  • El Hage K From the Department of Chemistry, University of Basel, Klingelbergstrasse 80 CH-4056 Basel, Switzerland.
  • Pandyarajan V the Departments of Biochemistry.
  • Phillips NB the Departments of Biochemistry.
  • Smith BJ the La Trobe Institute for Molecular Science, La Trobe University, Melbourne, Victoria 3086, Australia.
  • Menting JG the The Walter and Eliza Hall Institute of Medical Research, 1G Royal Parade, Parkville, Victoria 3052, Australia, and.
  • Whittaker J the Departments of Biochemistry.
  • Lawrence MC the The Walter and Eliza Hall Institute of Medical Research, 1G Royal Parade, Parkville, Victoria 3052, Australia, and.
  • Meuwly M From the Department of Chemistry, University of Basel, Klingelbergstrasse 80 CH-4056 Basel, Switzerland, m.meuwly@unibas.ch.
  • Weiss MA the Departments of Biochemistry, michael.weiss@case.edu.
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  • 2016-11-23
Published in:
  • The Journal of biological chemistry. - 2016
diabetes
diabetes mellitus
hormone
molecular dynamics
non-standard mutagenesis
quantum chemistry
quantum mechanics
weakly polar
Amino Acid Sequence
Chemistry, Pharmaceutical
Crystallography, X-Ray
Halogens
Humans
Hydrogen Bonding
Hydrophobic and Hydrophilic Interactions
Insulin
Models, Molecular
Phenylalanine
Protein Binding
Receptor, Insulin
Structure-Activity Relationship
Tyrosine
English 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.
Language
  • English
Open access status
bronze
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Persistent URL
https://sonar.ch/global/documents/149974
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