Sharma Akshit, Maurya Shweata, Tripathi Timir, Padhi Aditya K
Laboratory for Computational Biology & Biomolecular Design, School of Biochemical Engineering, Indian Institute of Technology (BHU), Varanasi, Uttar Pradesh 221005, India.
Molecular and Structural Biophysics Laboratory, Department of Zoology, North-Eastern Hill University, Shillong, India.
Acta Trop. 2024 Dec;260:107444. doi: 10.1016/j.actatropica.2024.107444. Epub 2024 Oct 28.
Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), responsible for the COVID-19 pandemic, is an enveloped, positive-stranded RNA virus that enters human cells by using its spike protein to bind to the human angiotensin-converting enzyme 2 (ACE2) receptor. Since its emergence, the virus has mutated, producing variants with increased transmissibility, immune evasion, and infectivity. The JN.1 variant, detected in January 2024, features a single substitution mutation (Leu455Ser) in the receptor-binding domain (RBD) of its spike protein, setting it apart from its parent lineage, BA.2.86. This variant has rapidly become globally predominant due to its enhanced transmission and significant epidemiological impact. To understand the causes behind the dominance of the JN.1 variant, we conducted a comprehensive study using all-atom molecular dynamics (MD) and coarse-grained MD simulations. This allowed us to examine the structural, dynamic, energetics and binding properties of the wild-type (Wuhan strain), BA.2.86, and JN.1 variants. Principal component and free energy landscape analyses revealed enhanced structural stability in the JN.1 variant. Molecular Mechanics Poisson-Boltzmann Surface Area (MM/PBSA) assessments indicated lower binding affinity for JN.1 as compared to BA.2.86. Intermolecular interaction analyses further confirmed BA.2.86's superior binding affinity over JN.1 and wild-type. Additionally, we compared and validated our findings against experimentally determined cryo-electron microscopy (cryo-EM) structures of JN.1 and BA.2.86 variants, confirming the reliability of our simulation results. Overall, this study provides crucial insights into the structural-dynamics-energetics features and physicochemical properties that have contributed to the global prevalence of the JN.1 variant and sheds light on its potential to generate future subvariants.
严重急性呼吸综合征冠状病毒2（SARS-CoV-2）引发了新冠疫情，它是一种有包膜的正链RNA病毒，通过其刺突蛋白与人血管紧张素转换酶2（ACE2）受体结合进入人体细胞。自出现以来，该病毒发生了变异，产生了传播性、免疫逃逸能力和传染性增强的变种。2024年1月检测到的JN.1变种在其刺突蛋白的受体结合域（RBD）中有一个单取代突变（Leu455Ser），使其与其亲本谱系BA.2.86有所不同。由于其传播能力增强和重大的流行病学影响，该变种迅速在全球占据主导地位。为了解JN.1变种占主导地位的原因，我们使用全原子分子动力学（MD）和粗粒度MD模拟进行了一项全面研究。这使我们能够研究野生型（武汉毒株）、BA.2.86和JN.1变种的结构、动力学、能量学和结合特性。主成分和自由能景观分析显示JN.1变种的结构稳定性增强。分子力学泊松-玻尔兹曼表面积（MM/PBSA）评估表明，与BA.2.86相比，JN.1的结合亲和力较低。分子间相互作用分析进一步证实BA.2.86对JN.1和野生型具有更高的结合亲和力。此外，我们将我们的研究结果与通过实验确定的JN.1和BA.2.86变种的冷冻电子显微镜（cryo-EM）结构进行了比较和验证，证实了我们模拟结果的可靠性。总体而言，这项研究为有助于JN.1变种在全球流行的结构-动力学-能量学特征和物理化学性质提供了关键见解，并揭示了其产生未来亚变种的可能性。
