Multiple SARS-CoV-2 variants have widely spread around the globe since the end of 2020, all carrying the common N501Y mutation at the receptor binding motif of the viral-surface spike protein. Experimental studies show that N501Y enhances viral binding to human angiotensin converting enzyme 2 (ACE2) and confers moderate resistance to certain monoclonal antibodies (mAbs). A mechanistic understanding of this mutation remains elusive. In this study, we used molecular dynamics simulation and alchemical free energy calculations, to systematically evaluate the effects of this prominent substitution on recognizing the host receptor ACE2 and different types of neutralizing mAbs. Our results suggest that this mutation alters the delicate local interaction with its binding partners: Y501 enhances local hydrophobicity, strengthens interaction with neighbouring K353 and Y41, and yields a ΔΔG_binding value of about −0.9 kcal mol⁻¹ to human ACE2, in quantitative agreement with the experimental measurement. Yet, N501Y diminishes the binding to cat ACE2 due to steric clash, indicating distinct transmissibility in different species. Meanwhile, the bulky Y501 reduces the binding to the antibody CB6 by about 4 folds, confirming recent experimental results. Intriguingly, the N501Y substitution fuses a larger hydrophobic core and sensitizes the binding to H014, which makes the viral strain more vulnerable to this typical antibody. The present study portraits the chemical nature of protein–protein interaction due to the SARS-CoV-2 spike protein mutation at atomic resolution and enlightens future investigations of other variants and vaccine design.

中文翻译：

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SARS-CoV-2 刺突蛋白 N501Y 突变导致不同物种传播性和抗体敏感性：分子动力学和炼金术自由能研究

自 2020 年底以来，多种 SARS-CoV-2 变体在全球范围内广泛传播，均在病毒表面刺突蛋白的受体结合基序上携带常见的 N501Y 突变。实验研究表明，N501Y 可增强病毒与人血管紧张素转化酶 2 (ACE2) 的结合，并赋予对某些单克隆抗体 (mAb) 的中等抵抗力。对这种突变的机制理解仍然难以捉摸。在这项研究中，我们使用分子动力学模拟和炼金术自由能计算来系统地评估这种突出的取代对识别宿主受体 ACE2 和不同类型的中和 mAb 的影响。我们的结果表明，这种突变改变了与其结合伙伴的微妙局部相互作用：Y501 增强了局部疏水性，G与人 ACE2 的_结合值为约 -0.9 kcal mol ^-1，与实验测量值定量一致。然而，由于空间冲突，N501Y 减少了与猫 ACE2 的结合，表明不同物种的传播能力不同。同时，庞大的 Y501 将与抗体 CB6 的结合降低了约 4 倍，证实了最近的实验结果。有趣的是，N501Y 取代融合了一个更大的疏水核心并使与 H014 的结合更加敏感，这使得病毒株更容易受到这种典型抗体的影响。本研究以原子分辨率描绘了由于 SARS-CoV-2 刺突蛋白突变引起的蛋白质-蛋白质相互作用的化学性质，并为未来对其他变体和疫苗设计的研究提供了启发。