da Costa Clauber Henrique Souza, de Freitas Camila Auad Beltrão, Dos Santos Alberto Monteiro, da Silva de Souza Carlos Gabriel, Silva José Rogério A, Lameira Jerônimo, Moliner Vicent, Skaf Munir S
Institute of Chemistry and Center for Computing in Engineering & Sciences, University of Campinas - UNICAMP, Campinas, SP 13084-862, Brazil.
Laboratório de Planejamento e Desenvolvimento de Fármacos, Instituto de Ciências Exatas e Naturais, Universidade Federal do Pará, Belém, Pará 66075-110, Brazil.
J Chem Inf Model. 2025 Jul 11. doi: 10.1021/acs.jcim.5c00308.
The SARS-CoV-2 virus, responsible for the COVID-19 pandemic, has continuously evolved, generating numerous variants with varying degrees of infectivity and transmissibility. The EG.5 subvariant of SARS-CoV-2 emerged globally in mid-2023 as part of the ongoing evolution of the Omicron lineage. Derived from the recombinant XBB.1.9 sublineage, EG.5 has attracted attention due to its enhanced immune escape and sustained transmissibility. As a member of the FLip lineage, EG.5 harbors the convergent F456L mutation in the spike receptor-binding domain (RBD), a key residue for neutralizing antibody recognition. Understanding the molecular mechanisms underlying these variations is crucial for developing effective antiviral strategies. In this study, we employed accelerated molecular dynamics simulations, free-energy calculations, and interaction fingerprint analysis, to investigate the intricate molecular interactions between the spike RBD and the angiotensin-converting enzyme 2 (ACE2) receptor in wild-type SARS-CoV-2 and its variants, specifically Omicron, XBB.1.9.2, and the concerning EG.5 variant. Our findings reveal that electrostatic interactions are the predominant driving force behind the stabilization of the viral spike protein-ACE2 complex. The Omicron, XBB.1.9.2, and EG.5 variants exhibit distinct electrostatic profiles at the spike-ACE2 interface, with mutations at key residues reconfiguring local interactions. These changes enhance ACE2 binding specificity and stabilize the spike-ACE2 complex through intensified electrostatic interactions. The EG.5 variant, with its stronger binding affinity to ACE2, underscores the ongoing threat posed by SARS-CoV-2. The F456L mutation in EG.5 enhances protein stability, further supporting its increased affinity for ACE2. Our research provides valuable insights for designing targeted antiviral therapies, including peptide inhibitors and bioactive compounds. Continuous research is essential to effectively combat COVID-19 and its evolving variants.
导致新冠疫情的严重急性呼吸综合征冠状病毒2（SARS-CoV-2）病毒不断进化，产生了许多具有不同感染性和传播性的变体。SARS-CoV-2的EG.5亚变体于2023年年中在全球出现，是奥密克戎谱系持续进化的一部分。EG.5源自重组XBB.1.9亚谱系，因其增强的免疫逃逸能力和持续的传播性而受到关注。作为FLip谱系的成员，EG.5在刺突受体结合域（RBD）中具有趋同的F456L突变，这是中和抗体识别的关键残基。了解这些变异背后的分子机制对于制定有效的抗病毒策略至关重要。在本研究中，我们采用加速分子动力学模拟、自由能计算和相互作用指纹分析，来研究野生型SARS-CoV-2及其变体，特别是奥密克戎、XBB.1.9.2和令人关注的EG.5变体中刺突RBD与血管紧张素转换酶2（ACE2）受体之间复杂的分子相互作用。我们的研究结果表明，静电相互作用是病毒刺突蛋白-ACE2复合物稳定的主要驱动力。奥密克戎、XBB.1.9.2和EG.5变体在刺突-ACE2界面呈现出不同的静电特征，关键残基的突变重新配置了局部相互作用。这些变化增强了ACE2结合特异性，并通过强化静电相互作用稳定了刺突-ACE2复合物。EG.5变体对ACE2具有更强的结合亲和力，凸显了SARS-CoV-2持续构成的威胁。EG.5中的F456L突变增强了蛋白质稳定性，进一步支持了其对ACE2亲和力的增加。我们的研究为设计靶向抗病毒疗法提供了有价值的见解，包括肽抑制剂和生物活性化合物。持续研究对于有效对抗新冠病毒及其不断演变的变体至关重要。
