Ks Sandhya, Nair Achuthsankar S
Department of Computational Biology and Bioinformatics, University of Kerala, Kerala, Thiruvananthapuram, India.
Malankara Catholic College, Mariagiri, Kaliakkavilai, Kanyakumari, 629153, Tamil Nadu, India.
J Genet Eng Biotechnol. 2023 Mar 20;21(1):35. doi: 10.1186/s43141-023-00492-y.
The existence of mutated Delta (B.1.617.2) variants of SARS-CoV-2 causes rapid transmissibility, increase in virulence, and decrease in the effectiveness of public health. Majority of mutations are seen in the surface spike, and they are considered as antigenicity and immunogenicity of the virus. Hence, finding suitable cross antibody or natural antibody and understanding its biomolecular recognition for neutralizing surface spike are crucial for developing many clinically approved COVID-19 vaccines. Here, we aim to design SARS-CoV-2 variant and hence, to understand its mechanism, binding affinity and neutralization potential with several antibodies.
In this study, we modelled six feasible spike protein (S1) configurations for Delta SARS-CoV-2 (B.1.617.2) and identified the best structure to interact with human antibodies. Initially, the impact of mutations at the receptor-binding domain (RBD) of B.1.617.2 was tested, and it is found that all mutations increase the stability of proteins (ΔΔG) and decrease the entropies. An exceptional case is noted for the mutation of G614D variant for which the vibration entropy change is found to be within the range of 0.133-0.004 kcal/mol/K. Temperature-dependent free energy change values (ΔG) for wild type is found to be - 0.1 kcal/mol, whereas all other cases exhibit values within the range of - 5.1 to - 5.5 kcal/mol. Mutation on spike increases the interaction with the glycoprotein antibody CR3022 and the binding affinity (CLUSpro energy = - 99.7 kcal/mol). The docked Delta variant with the following antibodies, etesevimab, bebtelovimab, BD-368-2, imdevimab, bamlanivimab, and casirivimab, exhibit a substantially decreased docking score (- 61.7 to - 112.0 kcal/mol) and the disappearance of several hydrogen bond interactions.
Characterization of antibody resistance for Delta variant with respect to the wild type gives understanding regarding why Delta variant endures the resistance boosted through several trademark vaccines. Several interactions with CR3022 have appeared compared to Wild for Delta variant, and hence, it is suggested that modification on the CR3022 antibody could further improve for the prevention of viral spread. Antibody resistance decreased significantly due to numerous hydrogen bond interactions which clearly indicate that these marketed/launched vaccines (etesevimab) will be effective for Delta variants.
严重急性呼吸综合征冠状病毒2（SARS-CoV-2）的变异德尔塔毒株（B.1.617.2）的存在导致其传播迅速、毒力增加以及公共卫生防控效果下降。大多数突变出现在表面刺突蛋白上，这些突变被认为与病毒的抗原性和免疫原性有关。因此，找到合适的交叉抗体或天然抗体并了解其对中和表面刺突蛋白的生物分子识别，对于开发许多临床批准的新冠疫苗至关重要。在此，我们旨在设计SARS-CoV-2变异毒株，并了解其与几种抗体的作用机制、结合亲和力和中和潜力。
在本研究中，我们对德尔塔SARS-CoV-2（B.1.617.2）的六种可行刺突蛋白（S1）构型进行了建模，并确定了与人类抗体相互作用的最佳结构。最初，测试了B.1.617.2受体结合域（RBD）处突变的影响，发现所有突变均增加了蛋白质的稳定性（ΔΔG）并降低了熵。G614D变异的突变是一个例外，其振动熵变在0.133 - 0.004千卡/摩尔/开尔文范围内。野生型的温度依赖性自由能变化值（ΔG）为-0.1千卡/摩尔，而所有其他情况的值在-5.1至-5.5千卡/摩尔范围内。刺突蛋白上的突变增加了与糖蛋白抗体CR3022的相互作用以及结合亲和力（CLUSpro能量 = -99.7千卡/摩尔）。将德尔塔变异毒株与以下抗体（etesevimab、bebtelovimab、BD-368-2、imdevimab、bamlanivimab和casirivimab）对接后，对接分数大幅降低（-61.7至-112.0千卡/摩尔），并且一些氢键相互作用消失。
对德尔塔变异毒株相对于野生型的抗体抗性进行表征，有助于理解为何德尔塔变异毒株能耐受几种标志性疫苗所激发的抗性。与野生型相比，德尔塔变异毒株与CR3022出现了几种相互作用，因此，建议对CR3022抗体进行修饰，以进一步改善对病毒传播 的预防。由于大量氢键相互作用，抗体抗性显著降低，这清楚地表明这些已上市/已推出的疫苗（etesevimab）对德尔塔变异毒株将是有效的。
