Division of Infectious disease and Division of Computer Aided Drug Design, The Red-Green Research Centre, Dhaka, Bangladesh.
Department of Chemistry and Biochemistry, Kennesaw State University, Kennesaw, GA, USA.
J Biomol Struct Dyn. 2024 Jul;42(11):5770-5787. doi: 10.1080/07391102.2023.2228919. Epub 2023 Jul 4.
The L84S mutation has been observed frequently in the ORF8 protein of SARS-CoV-2, which is an accessory protein involved in various important functions such as virus propagation, pathogenesis, and evading the immune response. However, the specific effects of this mutation on the dimeric structure of ORF8 and its impacts on interactions with host components and immune responses are not well understood. In this study, we performed one microsecond molecular dynamics (MD) simulation and analyzed the dimeric behavior of the L84S and L84A mutants in comparison to the native protein. The MD simulations revealed that both mutations caused changes in the conformation of the ORF8 dimer, influenced protein folding mechanisms, and affected the overall structural stability. In particular, the YIDI motif has found to be significantly affected by the L84S mutation, leading to structural flexibility in the region connecting the C-terminal β4 and β5 strands. This flexibility might be responsible for virus immune modulation. The free energy landscape (FEL) and principle component analysis (PCA) have also supported our investigation. Overall, the L84S and L84A mutations affect the ORF8 dimeric interfaces by reducing the frequency of protein-protein interacting residues (Arg52, Lys53, Arg98, Ile104, Arg115, Val117, Asp119, Phe120, and Ile121) in the ORF8 dimer. Our findings provide detail insights for further research in designing structure-based therapeutics against the SARS-CoV-2.Communicated by Ramaswamy H. Sarma.
L84S 突变已在 SARS-CoV-2 的 ORF8 蛋白中频繁观察到，该蛋白是一种辅助蛋白，参与病毒繁殖、发病机制和逃避免疫反应等多种重要功能。然而，这种突变对 ORF8 二聚体结构的具体影响及其对与宿主成分相互作用和免疫反应的影响尚不清楚。在这项研究中，我们进行了一秒钟的分子动力学 (MD) 模拟，并分析了 L84S 和 L84A 突变体与天然蛋白的二聚行为。MD 模拟表明，这两种突变都导致了 ORF8 二聚体构象的变化，影响了蛋白质折叠机制，并影响了整体结构稳定性。特别是 YIDI 基序已被发现受到 L84S 突变的显著影响，导致 C 端β4 和β5 链之间连接区的结构灵活性。这种灵活性可能是病毒免疫调节的原因。自由能景观 (FEL) 和主成分分析 (PCA) 也支持了我们的研究。总的来说，L84S 和 L84A 突变通过降低 ORF8 二聚体中相互作用残基（Arg52、Lys53、Arg98、Ile104、Arg115、Val117、Asp119、Phe120 和 Ile121）的频率来影响 ORF8 二聚体界面。我们的发现为设计针对 SARS-CoV-2 的基于结构的治疗方法提供了详细的见解。由 Ramaswamy H. Sarma 传达。
