Although the current coronavirus disease 2019 (COVID-19) vaccines have been used worldwide to halt spread of the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), the emergence of new SARS-CoV-2 variants with E484K mutation shows significant resistance to the neutralization of vaccine sera. To better understand the resistant mechanism, we calculated the binding affinities of 26 antibodies to wild-type (WT) spike protein and to the protein harboring E484K mutation, respectively. The results showed that most antibodies (~85%) have weaker binding affinities to the E484K mutated spike protein than to the WT, indicating the high risk of immune evasion of the mutated virus from most of current antibodies. Binding free energy decomposition revealed that the residue E484 forms attraction with most antibodies, while the K484 has repulsion from most antibodies, which should be the main reason of the weaker binding affinities of E484K mutant to most antibodies. Impressively, a monoclonal antibody (mAb) combination was found to have much stronger binding affinity with E484K mutant than WT, which may work well against the mutated virus. Based on binding free energy decomposition, we predicted that the mutation of four more residues on receptor-binding domain (RBD) of spike protein, viz., F490, V483, G485 and S494, may have high risk of immune evasion, which we should pay close attention on during the development of new mAb therapeutics.

中文翻译：

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通过分子动力学模拟探索携带 E484K 的 SARS-CoV-2 变体的免疫逃避

尽管目前的冠状病毒病 2019 (COVID-19) 疫苗已在全球范围内用于阻止严重急性呼吸系统综合症冠状病毒 2 (SARS-CoV-2) 的传播，但具有 E484K 突变的新 SARS-CoV-2 变体的出现显示出显着对疫苗血清中和的抵抗力。为了更好地了解耐药机制，我们分别计算了 26 种抗体与野生型 (WT) 刺突蛋白和含有 E484K 突变的蛋白质的结合亲和力。结果表明，大多数抗体 (~85%) 对 E484K 突变刺突蛋白的结合亲和力低于对 WT 的结合亲和力，这表明突变病毒免疫逃避大多数当前抗体的高风险。结合自由能分解表明残基 E484 与大多数抗体形成吸引力，而K484对大多数抗体有排斥作用，这应该是E484K突变体对大多数抗体结合亲和力较弱的主要原因。令人印象深刻的是，发现单克隆抗体 (mAb) 组合与 E484K 突变体的结合亲和力比 WT 强得多，这可能对突变病毒有效。基于结合自由能分解，我们预测刺突蛋白受体结合域（RBD）上的四个残基，即F490，V483，G485和S494的突变可能具有较高的免疫逃避风险，我们应该密切关注新的单克隆抗体疗法的开发过程。发现单克隆抗体 (mAb) 组合与 E484K 突变体的结合亲和力比 WT 强得多，这可能对突变病毒有效。基于结合自由能分解，我们预测刺突蛋白受体结合域（RBD）上的四个残基，即F490，V483，G485和S494的突变可能具有较高的免疫逃避风险，我们应该密切关注新的单克隆抗体疗法的开发过程。发现单克隆抗体 (mAb) 组合与 E484K 突变体的结合亲和力比 WT 强得多，这可能对突变病毒有效。基于结合自由能分解，我们预测刺突蛋白受体结合域（RBD）上的四个残基，即F490，V483，G485和S494的突变可能具有较高的免疫逃避风险，我们应该密切关注新的单克隆抗体疗法的开发过程。