Structure and interaction of therapeutic proteins in solution: a combined simulation and experimental study.
Structure and interaction of therapeutic proteins in solution: a combined simulation and experimental study.
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DOI：
10.1080/00268976.2023.2236248
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发表时间：
2023
影响因子：
1.7
通讯作者：
Bresme, Fernando
中科院分区：
文献类型：
--
作者：
Saurabh, Suman;Li, Zongyi;Hollowell, Peter;Waigh, Thomas;Li, Peixun;Webster, John;Seddon, John M. M.;Kalonia, Cavan;Lu, Jian R. R.;Bresme, Fernando
治疗性蛋白质在溶液中的聚集引起了人们极大的兴趣，推动人们努力了解微观结构变化与蛋白质-蛋白质相互作用之间的关系，从而确定溶液中的聚集过程。此外，人们对能够基于蛋白质结构预测聚集作为分子可开发性评估的一部分非常感兴趣。分子动力学提供了理论工具，以补充实验研究，并询问和确定微观机制决定聚集。在这里，我们进行全原子分子动力学模拟研究的单克隆抗体（mAb）COE 3的Fab和Fc片段的结构和蛋白质间的相互作用。我们解开的作用，离子蛋白质的相互作用，建立离子双电层，并确定有效的蛋白质间的相互作用。此外，我们证明，使用各种国家的最先进的力场（charmm，gromos，琥珀，opls/aa），蛋白质溶剂化，离子结构和蛋白质-蛋白质相互作用显着依赖于力场参数。我们进行SANS和静态光散射实验，以评估不同力场的准确性。模拟和实验结果的比较显示力场的性能，特别是在他们的能力，以预测蛋白质的大小在解决方案和蛋白质间的相互作用量化通过第二维里系数的显着差异。此外，力场的性能与蛋白质水合结构相关。
The aggregation of therapeutic proteins in solution has attracted significant interest, driving efforts to understand the relationship between microscopic structural changes and protein-protein interactions determining aggregation processes in solution. Additionally, there is substantial interest in being able to predict aggregation based on protein structure as part of molecular developability assessments. Molecular Dynamics provides theoretical tools to complement experimental studies and to interrogate and identify the microscopic mechanisms determining aggregation. Here we perform all-atom MD simulations to study the structure and inter-protein interaction of the Fab and Fc fragments of the monoclonal antibody (mAb) COE3. We unravel the role of ion-protein interactions in building the ionic double layer and determining effective inter-protein interaction. Further, we demonstrate, using various state-of-the-art force fields (charmm, gromos, amber, opls/aa), that the protein solvation, ionic structure and protein-protein interaction depend significantly on the force field parameters. We perform SANS and Static Light Scattering experiments to assess the accuracy of the different forcefields. Comparison of the simulated and experimental results reveal significant differences in the forcefields' performance, particularly in their ability to predict the protein size in solution and inter-protein interactions quantified through the second virial coefficients. In addition, the performance of the forcefields is correlated with the protein hydration structure.
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