胰岛素,一种对代谢稳态至关重要的蛋白质,为蛋白质设计提供了一个经典模型,并应用于人类健康。最近改善其药物制剂的努力表明,保守酪氨酸(TyrB26)的碘化可增强速效临床类似物的关键特性。此外,卤素在药物化学中的广泛用途促使人们使用混合量子和分子机械方法来研究蛋白质。这里,我们(I)对3-[碘-TyrB26]胰岛素进行了定量原子模拟,以预测其结构特征,(ii)通过X射线晶体学测试了这些预测。使用基于量子化学的改性芳环的静电模型,计算表明,模拟,作为二聚体和六聚体,在二聚体界面处显示出芳香-芳香相互作用的细微差异。在该界面处的芳香环(TyrB16,PheB24,PheB25,3-I-TyrB26及其对称相关的配对)进行调节,以使疏水碘原子堆积在每个单体的核心中。引人注目的是,在3-[碘-TyrB26]胰岛素类似物(测定为R6锌六聚体)的晶体结构中观察到这些特征。鉴于残基B24-B30在受体结合上与核心分离,受体复合物中3-I-TyrB26的环境必须与游离激素中的环境不同。根据最近的“微受体”复合物的结构,我们预测3-I-TyrB26通过定向卤键和卤素定向氢键与受体接合如下:利用有利的静电相互作用,分别,卤素的缺电子σ-空穴和电负性赤道带。受量子化学和分子动力学的启发,这种“卤素工程”有望将药物化学原理扩展到蛋白质。
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.