Structural Biology & Bioinformatics Laboratory, Department of Biosciences, Manipal University Jaipur, Dehmi Kalan, Off Jaipur-Ajmer Expressway, Jaipur, Rajasthan, 303007, India.
J Comput Aided Mol Des. 2023 Nov;37(11):551-563. doi: 10.1007/s10822-023-00526-0. Epub 2023 Aug 5.
Omicron derived lineages viz. BA.2, BA.3, BA.4 BA.5, BF.7 and XBBs show prominence with improved immune escape, transmissibility, infectivity, and pathogenicity in general. Sub-variants, XBB.1.5 and XBB.1.16 have shown rapid spread, with mutations embedded throughout the viral genome, including the spike protein. Changing atomic landscapes in spike contributes significantly to modulate host pathogen interactions and infections thereof. In the present work, we computationally analyzed the binding affinities of spike receptor binding domains (RBDs) of XBB.1.5 and XBB.1.16 towards human angiotensin-converting enzyme 2 (hACE2) compared to Omicron. We have employed simulations and binding energy estimation of molecular complexes of spike-hACE2 to assess the interplay of interaction pattern and effect of mutations if any in the binding mode of the RBDs of these novel mutants. We calculated the binding free energy (BFE) of the RBD of the Omicron, XBB.1.5 and XBB.1.16 spike protein to hACE2. We showed that XBB.1.5 and XBB.1.16 can bind to human cells more strongly than Omicron due to the increased charge of the RBD, which enhances the electrostatic interactions with negatively charged hACE2. The per-residue decompositions further show that the Asp339His, Asp405Asn and Asn460Lys mutations in the XBBs RBD play a crucial role in enhancing the electrostatic interactions, by acquiring positively charged residues, thereby influencing the formation/loss of interfacial bonds and thus strongly affecting the spike RBD-hACE2 binding affinity. Simulation results also indicate less interference of heterogeneous glycans of XBB.1.5 spike RBD towards binding to hACE2. Moreover, despite having less interaction at the three interfacial contacts between XBB S RBD and hACE2 compared to Omicron, variants XBB.1.5 and XBB.1.16 had higher total binding free energies (ΔG) than Omicron due to the contribution of non-interfacial residues to the free energy, providing insight into the increased binding affinity of XBB1.5 and XBB.1.16. Furthermore, the presence of large positively charged surface patches in the XBBs act as drivers of electrostatic interactions, thus support the possibility of a higher binding affinity to hACE2.
奥密克戎衍生谱系，如 BA.2、BA.3、BA.4、BA.5、BF.7 和 XBBs，通常具有更好的免疫逃逸、传染性、感染力和致病性。亚变体 XBB.1.5 和 XBB.1.16 表现出快速传播，其病毒基因组中包括刺突蛋白在内的多个突变。刺突中改变的原子景观对调节宿主病原体相互作用和感染有重要贡献。在本工作中，我们通过计算分析了 XBB.1.5 和 XBB.1.16 的刺突受体结合域（RBD）与奥密克戎相比与人类血管紧张素转化酶 2（hACE2）的结合亲和力。我们采用了模拟和分子复合物结合能估计的方法，评估了这些新型突变体的 RBD 结合模式中的相互作用模式和突变的影响。我们计算了奥密克戎、XBB.1.5 和 XBB.1.16 刺突蛋白的 RBD 与 hACE2 的结合自由能（BFE）。我们发现，由于 RBD 的电荷增加，XBB.1.5 和 XBB.1.16 可以比奥密克戎更强烈地与人类细胞结合，从而增强与带负电荷的 hACE2 的静电相互作用。逐残基分解进一步表明，XBBs RBD 中的 Asp339His、Asp405Asn 和 Asn460Lys 突变通过获得带正电荷的残基在增强静电相互作用方面起着至关重要的作用，从而影响界面键的形成/丢失，从而强烈影响刺突 RBD-hACE2 的结合亲和力。模拟结果还表明，XBB.1.5 刺突 RBD 上异质聚糖对与 hACE2 结合的干扰较小。此外，尽管与奥密克戎相比，XBB.1.5 和 XBB.1.16 变体在 XBB S RBD 和 hACE2 之间的三个界面接触处的相互作用较少，但由于非界面残基对自由能的贡献，变体 XBB.1.5 和 XBB.1.16 的总结合自由能（ΔG）更高，这为 XBB1.5 和 XBB.1.16 结合亲和力的增加提供了依据。此外，XBBs 中带正电荷的表面斑块的存在充当静电相互作用的驱动因素，因此支持与 hACE2 更高结合亲和力的可能性。
