Horx Philip, Geyer Armin
Faculty of Organic Chemistry, Philipps-University, Marburg, Germany.
Front Chem. 2020 Jan 28;8:25. doi: 10.3389/fchem.2020.00025. eCollection 2020.
A pair of intermolecular disulfide bonds connecting two protein domains restricts their relative mobility in a systematic way. The bi-disulfide hinge cannot rotate like a single intermolecular disulfide bond yet is less restrained than three or more intermolecular disulfides which restrict the relative motion to a minimum. The intermediate mobility of bi-disulfide linked domains is characterized by their dominating opening and closing modes comparable to the mechanics of a door hinge on the macroscopic scale. Here we compare the central hinge region of Immunoglobulin G1 (IgG1) which is highly conserved among different species, with a recently designed hinge-type motif CHWECRGCRLVC from our lab, that was successfully used for the dimerization of the IgG1/κ-ab CL4 monocolonal antibody (mab). The minimal length of these synthetic hinges comprises only 12 amino acids, rendering them ideal models for computational studies. Well-tempered metadynamics was performed to adequately describe the available conformational space defined by the different hinges. In spite of the differences in amino acid composition and ring sizes, there are characteristic similarities of designed and natural hinges like the dependent mobility of the individual strands of each hinge domain.
连接两个蛋白质结构域的一对分子间二硫键以一种系统的方式限制了它们的相对移动性。双二硫键铰链不像单个分子间二硫键那样能够旋转，但比三个或更多分子间二硫键的限制要小，后者会将相对运动限制到最小程度。双二硫键连接的结构域的中间移动性的特征在于其主要的打开和关闭模式，这与宏观尺度上门铰链的力学原理类似。在这里，我们将在不同物种中高度保守的免疫球蛋白G1（IgG1）的中央铰链区与我们实验室最近设计的铰链型基序CHWECRGCRLVC进行比较，该基序已成功用于IgG1/κ-ab CL4单克隆抗体（mab）的二聚化。这些合成铰链的最小长度仅包含12个氨基酸，使其成为计算研究的理想模型。我们进行了温度加速分子动力学模拟，以充分描述由不同铰链定义的可用构象空间。尽管氨基酸组成和环大小存在差异，但设计的铰链和天然铰链具有特征性的相似之处，例如每个铰链结构域的各个链的依赖性移动性。
