Bhadane Rajendra, Salo-Ahen Outi M H
Structural Bioinformatics Laboratory, Faculty of Science and Engineering, Biochemistry, Åbo Akademi University, FI-20520 Turku, Finland.
Pharmaceutical Sciences Laboratory, Faculty of Science and Engineering, Pharmacy, Åbo Akademi University, FI-20520 Turku, Finland.
Biomedicines. 2022 Nov 1;10(11):2779. doi: 10.3390/biomedicines10112779.
The ongoing pandemic caused by SARS-CoV-2 has gone through various phases. Since the initial outbreak, the virus has mutated several times, with some lineages showing even stronger infectivity and faster spread than the original virus. Among all the variants, omicron is currently classified as a variant of concern (VOC) by the World Health Organization, as the previously circulating variants have been replaced by it. In this work, we have focused on the mutations observed in omicron sub lineages BA.1, BA.2, BA.4 and BA.5, particularly at the receptor-binding domain (RBD) of the spike protein that is responsible for the interactions with the host ACE2 receptor and binding of antibodies. Studying such mutations is particularly important for understanding the viral infectivity, spread of the disease and for tracking the escape routes of this virus from antibodies. Molecular dynamics (MD) based alchemical free energy calculations have been shown to be very accurate in predicting the free energy change, due to a mutation that could have a deleterious or a stabilizing effect on either the protein itself or its binding affinity to another protein. Here, we investigated the significance of five spike RBD mutations on the stability of the spike protein binding to ACE2 by free energy calculations using high throughput MD simulations. For comparison, we also used conventional MD simulations combined with a Molecular Mechanics-Generalized Born Surface Area (MM-GBSA) based approach, and compared our results with the available experimental data. Overall, the alchemical free energy calculations performed far better than the MM-GBSA approach in predicting the individual impact of the mutations. When considering the experimental variation, the alchemical free energy method was able to produce a relatively accurate prediction for N501Y, the mutant that has previously been reported to increase the binding affinity to hACE2. On the other hand, the other individual mutations seem not to have a significant effect on the spike RBD binding affinity towards hACE2.
由严重急性呼吸综合征冠状病毒2（SARS-CoV-2）引发的持续大流行已经历了多个阶段。自最初爆发以来，该病毒已经发生了多次变异，一些谱系表现出比原始病毒更强的传染性和更快的传播速度。在所有变异株中，奥密克戎目前被世界卫生组织列为值得关注的变异株（VOC），因为它已经取代了先前流行的变异株。在这项工作中，我们重点研究了在奥密克戎亚谱系BA.1、BA.2、BA.4和BA.5中观察到的突变，特别是在刺突蛋白的受体结合域（RBD），该区域负责与宿主血管紧张素转换酶2（ACE2）受体相互作用以及与抗体结合。研究此类突变对于理解病毒的传染性、疾病传播以及追踪该病毒逃避抗体的途径尤为重要。基于分子动力学（MD）的炼金术自由能计算已被证明在预测由于可能对蛋白质本身或其与另一种蛋白质的结合亲和力产生有害或稳定作用的突变而导致的自由能变化方面非常准确。在这里，我们通过高通量MD模拟进行自由能计算，研究了刺突RBD五个突变对刺突蛋白与ACE₂结合稳定性的影响。为了进行比较，我们还使用了传统的MD模拟结合基于分子力学-广义玻恩表面积（MM-GBSA） 的方法，并将我们的结果与现有的实验数据进行了比较。总体而言，炼金术自由能计算在预测突变的个体影响方面比MM-GBSA方法表现得好得多。考虑到实验变化时，炼金术自由能方法能够对N501Y产生相对准确的预测，此前有报道称该突变体增加了与人类ACE2的结合亲和力。另一方面，其他单个突变似乎对刺突RBD与人类ACE₂的结合亲和力没有显著影响。
