Olivos-Ramirez Gustavo E, Cofas-Vargas Luis F, Madl Tobias, Poma Adolfo B
Department of Biosystems and Soft Matter, Institute of Fundamental Technological Research, Polish Academy of Sciences, ul. Pawińskiego 5B, 02-106 Warsaw, Poland.
Division of Medical Chemistry, Otto Loewi Research Center for Vascular Biology, Immunology and Inflammation, Medical University of Graz, Neue Stiftingtalstraße 6, 8010 Graz, Austria.
Pathogens. 2025 Mar 12;14(3):274. doi: 10.3390/pathogens14030274.
We performed a comprehensive structural analysis of the conformational space of several spike (S) protein variants using molecular dynamics (MD) simulations. Specifically, we examined four well-known variants (Delta, BA.1, XBB.1.5, and JN.1) alongside the wild-type (WT) form of SARS-CoV-2. The conformational states of each variant were characterized by analyzing their distributions within a selected space of collective variables (CVs), such as inter-domain distances between the receptor-binding domain (RBD) and the N-terminal domain (NTD). Our primary focus was to identify conformational states relevant to potential structural transitions and to determine the set of native contacts (NCs) that stabilize these conformations. The results reveal that genetically more distant variants, such as XBB.1.5, BA.1, and JN.1, tend to adopt more compact conformational states compared to the WT. Additionally, these variants exhibit novel NC profiles, characterized by an increased number of specific contacts distributed among ionic, polar, and nonpolar residues. We further analyzed the impact of specific mutations, including T478K, N500Y, and Y504H. These mutations not only enhance interactions with the human host receptor but also alter inter-chain stability by introducing additional NCs compared to the WT. Consequently, these mutations may influence the accessibility of certain protein regions to neutralizing antibodies. Overall, these findings contribute to a deeper understanding of the structural and functional variations among S protein variants.
我们使用分子动力学（MD）模拟对几种刺突（S）蛋白变体的构象空间进行了全面的结构分析。具体而言，我们研究了四种著名的变体（德尔塔、BA.1、XBB.1.5和JN.1）以及严重急性呼吸综合征冠状病毒2（SARS-CoV-2）的野生型（WT）形式。通过分析每个变体在选定的集体变量（CV）空间内的分布来表征其构象状态，这些集体变量例如受体结合域（RBD）和N端结构域（NTD）之间的结构域间距离。我们的主要重点是确定与潜在结构转变相关的构象状态，并确定稳定这些构象的天然接触（NC）集。结果表明，与野生型相比，遗传距离更远的变体，如XBB.1.5、BA.1和JN.1，倾向于采用更紧凑的构象状态。此外，这些变体表现出新颖的天然接触图谱，其特征是在离子、极性和非极性残基之间分布的特定接触数量增加。我们进一步分析了特定突变的影响，包括T478K、N500Y和Y504H。这些突变不仅增强了与人类宿主受体的相互作用，还通过引入与野生型相比额外的天然接触来改变链间稳定性。因此，这些突变可能会影响某些蛋白质区域对中和抗体的可及性。总体而言，这些发现有助于更深入地理解S蛋白变体之间的结构和功能差异。
