Higher Affinity Antibodies Bind With Lower Hydration and Flexibility in Large Scale Simulations.
Higher Affinity Antibodies Bind With Lower Hydration and Flexibility in Large Scale Simulations.
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DOI：
10.3389/fimmu.2022.884110
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发表时间：
2022
影响因子：
7.3
通讯作者：
中科院分区：
文献类型：
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作者：
我们已经进行了长时间尺度的模拟研究的晶体结构的9个抗体-抗原对，在抗原结合和抗体的形式，使用分子动力学与增强采样和明确的水模型，以探索界面构象和水合作用。通过结合原子水平的模拟和副本交换，使充分的蛋白质的灵活性，我们发现大量的桥接水分子在抗体-抗原界面。此外，排除本体沃茨的更高比例的相互作用和更低程度的抗原结合CDR构象采样与更高的抗体亲和力相关。CDR采样支持与熵驱动相反的熵驱动的抗体结合，因为抗原结合和未结合构象之间的差异与亲和力不相关。因此，我们提出，与沃茨和CDR采样的相互作用是界面的方面，可能会缓和抗体-抗原结合，明确的水化和CDR的灵活性，应考虑改善抗体亲和力预测和计算设计工作流程。
We have carried out a long-timescale simulation study on crystal structures of nine antibody-antigen pairs, in antigen-bound and antibody-only forms, using molecular dynamics with enhanced sampling and an explicit water model to explore interface conformation and hydration. By combining atomic level simulation and replica exchange to enable full protein flexibility, we find significant numbers of bridging water molecules at the antibody-antigen interface. Additionally, a higher proportion of interactions excluding bulk waters and a lower degree of antigen bound CDR conformational sampling are correlated with higher antibody affinity. The CDR sampling supports enthalpically driven antibody binding, as opposed to entropically driven, in that the difference between antigen bound and unbound conformations do not correlate with affinity. We thus propose that interactions with waters and CDR sampling are aspects of the interface that may moderate antibody-antigen binding, and that explicit hydration and CDR flexibility should be considered to improve antibody affinity prediction and computational design workflows.
影响因子：
2.9
作者：
Killikelly, April;Zhang, Hui-Tang;Spurrier, Brett;Williams, Constance;Gorny, Miroslaw K.;Zolla-Pazner, Susan;Kong, Xiang-Peng
通讯作者：
Kong, Xiang-Peng
抗肽抗体对天然蛋白识别的结构和热力学见解。
影响因子：
5.6
作者：
Armstrong, Anthony A.;Hildreth, James E. K.;Amzel, L. Mario
通讯作者：
Amzel, L. Mario