Departamento de Ciências Biomoleculares, Faculdade de Ciências Farmacêuticas de Ribeirão Preto, Universidade de São Paulo, Av. café, s/no-campus da USP, BR-14040-903 Ribeirão Preto, SP, Brazil.
Department of Chemical and Biomolecular Engineering, North Carolina State University, Raleigh, North Carolina 27695, United States.
J Phys Chem B. 2022 Sep 15;126(36):6835-6852. doi: 10.1021/acs.jpcb.2c04225. Epub 2022 Sep 6.
Electrostatic intermolecular interactions are important in many aspects of biology. We have studied the main electrostatic features involved in the interaction of the receptor-binding domain (RBD) of the SARS-CoV-2 spike protein with the human receptor Angiotensin-converting enzyme 2 (ACE2). As the principal computational tool, we have used the FORTE approach, capable to model proton fluctuations and computing free energies for a very large number of protein-protein systems under different physical-chemical conditions, here focusing on the RBD-ACE2 interactions. Both the wild-type and all critical variants are included in this study. From our large ensemble of extensive simulations, we obtain, as a function of pH, the binding affinities, charges of the proteins, their charge regulation capacities, and their dipole moments. In addition, we have calculated the ps for all ionizable residues and mapped the electrostatic coupling between them. We are able to present a simple predictor for the RBD-ACE2 binding based on the data obtained for Alpha, Beta, Gamma, Delta, and Omicron variants, as a linear correlation between the total charge of the RBD and the corresponding binding affinity. This "RBD charge rule" should work as a quick test of the degree of severity of the coming SARS-CoV-2 variants in the future.
静电分子间相互作用在生物学的许多方面都很重要。我们研究了 SARS-CoV-2 刺突蛋白受体结合域（RBD）与人类受体血管紧张素转换酶 2（ACE2）相互作用涉及的主要静电特征。作为主要的计算工具，我们使用了 FORTE 方法，该方法能够在不同的物理化学条件下对大量的蛋白质-蛋白质体系进行质子波动建模和自由能计算，这里重点研究了 RBD-ACE2 的相互作用。本研究包括野生型和所有关键变体。从我们广泛的模拟大型集合中，我们获得了 pH 依赖性的结合亲和力、蛋白质电荷、电荷调节能力和偶极矩。此外，我们还计算了所有可离子化残基的 ps 值，并绘制了它们之间的静电耦合图。我们能够基于对 Alpha、Beta、Gamma、Delta 和 Omicron 变体获得的数据，提出一个基于 RBD-ACE2 结合的简单预测器，即 RBD 总电荷与相应结合亲和力之间的线性相关性。这个“RBD 电荷规则”应该可以作为未来 SARS-CoV-2 变体严重程度的快速测试。
