Thomas C. Jenkins Department of Biophysics, Johns Hopkins University, Baltimore, Maryland.
Department of Cell and Molecular Biology, University of Mississippi Medical Center, Jackson, Mississippi.
Biophys J. 2024 Aug 20;123(16):2379-2391. doi: 10.1016/j.bpj.2024.05.019. Epub 2024 May 22.
Polyethylene glycol (PEG) conjugation provides a protective modification that enhances the pharmacokinetics and solubility of proteins for therapeutic use. A knowledge of the structural ensemble of these PEGylated proteins is necessary to understand the molecular details that contribute to their hydrodynamic and colligative properties. Because of the large size and dynamic flexibility of pharmaceutically important PEGylated proteins, the determination of structure is challenging. In addition, the hydration of these conjugates that contain large polymers is difficult to determine with traditional methods that identify only first shell hydration water, which does not account for the complete hydrodynamic volume of a macromolecule. Here, we demonstrate that structural ensembles, generated by coarse-grained simulations, can be analyzed with HullRad and used to predict sedimentation coefficients and concentration-dependent hydrodynamic and diffusion nonideality coefficients of PEGylated proteins. A knowledge of these concentration-dependent properties enhances the ability to design and analyze new modified protein therapeutics. HullRad accomplishes this analysis by effectively accounting for the complete hydration of a macromolecule, including that of flexible polymers.
聚乙二醇（PEG）缀合提供了一种保护修饰，可增强蛋白质的药代动力学和溶解度，用于治疗用途。为了了解这些聚乙二醇化蛋白质的流体力学和依数性质的分子细节，需要了解其结构整体。由于具有重要药用价值的聚乙二醇化蛋白质的体积大且动态灵活，因此确定其结构具有挑战性。此外，这些包含大聚合物的缀合物的水合作用很难用传统方法确定，因为传统方法只能识别仅与第一壳层水合的水，而不能说明大分子的完整流体力学体积。在这里，我们证明了通过粗粒度模拟生成的结构整体可以用 HullRad 进行分析，并用于预测聚乙二醇化蛋白质的沉降系数以及浓度依赖性流体力学和扩散非理想系数。了解这些浓度依赖性性质可增强设计和分析新型修饰蛋白治疗药物的能力。HullRad 通过有效地考虑大分子的完整水合作用（包括灵活聚合物的水合作用）来完成此分析。
