title: Extending Halogen-based Medicinal Chemistry to Proteins: IODO-INSULIN AS A CASE STUDY.
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 R6zinc hexamer). Given that residues B24-B30 detach from the core on receptor binding, the environment of 3-I-TyrB26in 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-TyrB26engages 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.
authors.affiliation: From the Department of Chemistry, University of Basel, Klingelbergstrasse 80 CH-4056 Basel, Switzerland.
authors.forename: Krystel
authors.initials: K
authors.lastname: El Hage
authors.affiliation: the Departments of Biochemistry.
authors.forename: Vijay
authors.initials: V
authors.lastname: Pandyarajan
authors.affiliation: the Departments of Biochemistry.
authors.forename: Nelson B
authors.initials: NB
authors.lastname: Phillips
authors.affiliation: the La Trobe Institute for Molecular Science, La Trobe University, Melbourne, Victoria 3086, Australia.
authors.forename: Brian J
authors.initials: BJ
authors.lastname: Smith
authors.affiliation: the The Walter and Eliza Hall Institute of Medical Research, 1G Royal Parade, Parkville, Victoria 3052, Australia, and.
authors.forename: John G
authors.initials: JG
authors.lastname: Menting
authors.affiliation: the Departments of Biochemistry.
authors.forename: Jonathan
authors.initials: J
authors.lastname: Whittaker
authors.affiliation: the The Walter and Eliza Hall Institute of Medical Research, 1G Royal Parade, Parkville, Victoria 3052, Australia, and.|the Department of Medical Biology, University of Melbourne, Parkville, Victoria 3010, Australia.
authors.forename: Michael C
authors.initials: MC
authors.lastname: Lawrence
authors.affiliation: From the Department of Chemistry, University of Basel, Klingelbergstrasse 80 CH-4056 Basel, Switzerland, m.meuwly@unibas.ch.
authors.forename: Markus
authors.initials: M
authors.lastname: Meuwly
authors.affiliation: the Departments of Biochemistry, michael.weiss@case.edu.|Medicine, and.|Biomedical Engineering, Case Western Reserve University, Cleveland, Ohio 44106.
authors.forename: Michael A
authors.initials: MA
authors.lastname: Weiss
mesh_terms: D000595:Amino Acid Sequence; D002626:Chemistry, Pharmaceutical; D018360:Crystallography, X-Ray; D006219:Halogens; D006801:Humans; D006860:Hydrogen Bonding; D057927:Hydrophobic and Hydrophilic Interactions; D007328:Insulin / Q000031:analogs & derivatives* / Q000737:chemistry / Q000235:genetics / Q000378:metabolism; D008958:Models, Molecular; D010649:Phenylalanine / Q000737:chemistry / Q000235:genetics / Q000378:metabolism; D011485:Protein Binding; D011972:Receptor, Insulin / Q000737:chemistry / Q000378:metabolism*; D013329:Structure-Activity Relationship; D014443:Tyrosine / Q000737:chemistry / Q000235:genetics / Q000378:metabolism
chemical_list: D006219:Halogens; D007328:Insulin; C008147:insulin, iodo-; D014443:Tyrosine; D010649:Phenylalanine; D011972:Receptor, Insulin
keywords: diabetes; diabetes mellitus; hormone; molecular dynamics; non-standard mutagenesis; quantum chemistry; quantum mechanics; weakly polar