When the Dust Has Settled: Calculation of Binding Affinities from First Principles for SARS-CoV-2 Variants with Quantitative Accuracy
When the Dust Has Settled: Calculation of Binding Affinities from First Principles for SARS-CoV-2 Variants with Quantitative Accuracy
复制标题
DOI：
10.1021/acs.jctc.2c00604
复制
发表时间：
2022-09-15
影响因子：
5.5
通讯作者：
Chipot, Christophe
中科院分区：
文献类型：
--
作者：
de Lacam, Emma Goulard Coderc;Blazhynska, Marharyta;Chipot, Christophe
结合自由能的准确测定对许多生物过程的研究至关重要，并已应用于许多理论研究，以比较严重急性呼吸综合征冠状病毒2变异对宿主细胞的亲和力。这些变异的多样性挑战了有效的一般治疗方法的发展，它们的传播依赖于对其专用的人类受体血管紧张素转换酶2 （ACE2）的亲和力增加，或者逃避免疫反应。现在有了可靠的结构数据，我们已经非常准确地确定了受体结合域的标准结合自由能，以最广泛的变体，即Alpha， Beta， Delta和Omicron BA.2，以及野生型（WT）复合物，无论是与ACE2还是与抗体，即S2E12和H11-D4，使用严格的理论框架，结合分子动力学和平均力势能计算。我们的研究结果表明，适当的起始结构对于确保结合亲和力的适当复制至关重要，从而允许对变体进行比较。他们还强调了应用相关方法的必要性，没有任何捷径，来解释对标准束缚自由能的所有贡献。我们对结合亲和力的估计支持这样的观点，即α和β变异体倾向于增加对宿主细胞的亲和力，而Delta和Omicron BA.2变异体选择免疫逃逸。此外，已知对WT有活性的S2E12抗体（Starr et al., 2021; Mlcochova et al., 2021）被证明对Delta变体同样有效。与此形成鲜明对比的是，与ACE2相比，H11-D4对WT的亲和力较低。假设结构信息稳健，本文采用的方法成功解决了2019冠状病毒病背景下具有挑战性的蛋白质-蛋白质结合问题，同时为不断出现的变异的预测研究提供了有希望的前景。
Accurate determination of binding free energy is pivotal for the study of many biological processes and has been applied in a number of theoretical investigations to compare the affinity of severe acute respiratory syndrome coronavirus 2 variants toward the host cell. Diversity of these variants challenges the development of effective general therapies, their transmissibility relying either on an increased affinity toward their dedicated human receptor, the angiotensin-converting enzyme 2 (ACE2), or on escaping the immune response. Now that robust structural data are available, we have determined with utmost accuracy the standard binding free energy of the receptor-binding domain to the most widespread variants, namely, Alpha, Beta, Delta, and Omicron BA.2, as well as the wild type (WT) in complex either with ACE2 or with antibodies, namely, S2E12 and H11-D4, using a rigorous theoretical framework that combines molecular dynamics and potential-of-mean-force calculations. Our results show that an appropriate starting structure is crucial to ensure appropriate reproduction of the binding affinity, allowing the variants to be compared. They also emphasize the necessity to apply the relevant methodology, bereft of any shortcut, to account for all the contributions to the standard binding free energy. Our estimates of the binding affinities support the view that while the Alpha and Beta variants lean on an increased affinity toward the host cell, the Delta and Omicron BA.2 variants choose immune escape. Moreover, the S2E12 antibody, already known to be active against the WT (Starr et al., 2021; Mlcochova et al., 2021), proved to be equally effective against the Delta variant. In stark contrast, H11-D4 retains a low affinity toward the WT compared to that of ACE2 for the latter. Assuming robust structural information, the methodology employed herein successfully addresses the challenging protein-protein binding problem in the context of coronavirus disease 2019 while offering promising perspectives for predictive studies of ever-emerging variants.