Common framework mutations impact antibody interfacial dynamics and flexibility.
Common framework mutations impact antibody interfacial dynamics and flexibility.
复制标题
DOI：
10.3389/fimmu.2023.1120582
复制
发表时间：
2023
影响因子：
7.3
通讯作者：
中科院分区：
文献类型：
--
作者：
随着工程抗体的大量涌现，对阐明有助于特异性、稳定性和广度的抗体的结构特征的需求增加。虽然已经开始探索抗体的灵活性和界面角度，但设计规则尚未出现，因为它们对上述指标的影响仍不清楚。此外，成熟抗体中框架突变的目的是高度复杂的。为此，进行了利用分子动力学模拟的案例研究，以确定框架突变对VH-VL界面的影响。我们进一步试图通过观察均方根偏差、均方根波动和溶剂可及表面积来阐明VH-VL界面角的变化影响成熟抗体的结构元件的控制机制。总体而言，我们的结果表明框架突变可以显著改变VH-VL界面角的分布，这通过溶剂可及表面积的局部变化导致抗体柔性的局部变化。本文提供的数据强调了拒绝静态抗体晶体结构的教条的需要，并阐明了这些蛋白质在溶液中的动态性质。这项工作的发现进一步证明了框架突变对抗体结构的重要性，并为建立设计原则奠定了基础，以创建具有更高特异性，稳定性和广度的抗体。
With the flood of engineered antibodies, there is a heightened need to elucidate the structural features of antibodies that contribute to specificity, stability, and breadth. While antibody flexibility and interface angle have begun to be explored, design rules have yet to emerge, as their impact on the metrics above remains unclear. Furthermore, the purpose of framework mutations in mature antibodies is highly convoluted. To this end, a case study utilizing molecular dynamics simulations was undertaken to determine the impact framework mutations have on the VH-VL interface. We further sought to elucidate the governing mechanisms by which changes in the VH-VL interface angle impact structural elements of mature antibodies by looking at root mean squared deviations, root mean squared fluctuations, and solvent accessible surface area. Overall, our results suggest framework mutations can significantly shift the distribution of VH-VL interface angles, which leads to local changes in antibody flexibility through local changes in the solvent accessible surface area. The data presented herein highlights the need to reject the dogma of static antibody crystal structures and exemplifies the dynamic nature of these proteins in solution. Findings from this work further demonstrate the importance of framework mutations on antibody structure and lay the foundation for establishing design principles to create antibodies with increased specificity, stability, and breadth.