Nguyen Hung Van, Ngoc Lan Nguyen Le, Li Mai Suan
Institute of Physics, Polish Academy of Sciences, Al. Lotnikow 32/46, 02-668 Warsaw, Poland.
Biomedical Engineering Department, University of Technology-VNU HCM, 268 Ly Thuong Kiet Street, Ward 14, District 10, 740500 Ho Chi Minh City, Vietnam.
J Chem Inf Model. 2025 Aug 11;65(15):8276-8289. doi: 10.1021/acs.jcim.5c00999. Epub 2025 Jul 30.
A comprehensive understanding of the atomic level mechanism governing the binding nonstructural protein 1 of SARS-CoV-1 (SARS-CoV-1 NSP1) and SARS-CoV-2 (SARS-CoV-2 NSP1) to Pol α-primase is important to advance the development of small molecule inhibitors for the treatment COVID-19. In this study, we use both all-atom steered molecular dynamics (all-atom SMD) and coarse-grained umbrella sampling (coarse-grained US) simulations to assess the binding affinity of SARS-CoV-1 NSP1 and SARS-CoV-2 NSP1 to Pol α-primase. Our all-atom SMD and coarse-grained US simulations consistently indicate that SARS-CoV-2 NSP1 exhibits stronger affinity for Pol α-primase compared to SARS-CoV-1 NSP1, implying that SARS-CoV-2 poses a greater risk than SARS-CoV-1 in impeding DNA replication for DNA synthesis. Through an energetic decomposition analysis of the interaction energies within these complexes, we identify electrostatic interactions as the primary contributors to the observed difference in binding affinity. We found that hydrogen bonds between Asp33 and Arg616 in SARS1 NSP1-Pol α-primase, and Asp33 with Arg616 and Lys655 in SARS2 NSP1-Pol α-primase, are critical for the interaction of both SARS-CoV-1 NSP1 and SARS-CoV-2 NSP1 with Pol α-primase. Asp33 in SARS-CoV-2 NSP1 shows increased solubility and stability compared to SARS-CoV-1 NSP1, enhancing its association with Pol α-primase. This finding lays the groundwork for innovative strategies aimed at inhibiting the interaction between these entities, offering promising avenues for therapeutic intervention against COVID-19. We also estimated the binding free energy of DNA to Pol α-primase, SARS1 NSP1-Pol α-primase, and SARS2 NSP1-Pol α-primase using the MM-PBSA method. The results show the order: Pol α-primase-DNA < SARS1 NSP1-Pol α-primase-DNA < SARS2 NSP1-Pol α-primase-DNA, indicating that both SARS-CoV-1 NSP1 and SARS-CoV-2 NSP1 reduce DNA binding to Pol α-primase, suggesting impaired DNA synthesis.
全面了解控制严重急性呼吸综合征冠状病毒1（SARS-CoV-1）和严重急性呼吸综合征冠状病毒2（SARS-CoV-2）的非结构蛋白1与DNA聚合酶α-引发酶结合的原子水平机制，对于推进用于治疗新冠肺炎的小分子抑制剂的开发至关重要。在本研究中，我们使用全原子引导分子动力学（全原子SMD）和粗粒度伞形采样（粗粒度US）模拟来评估SARS-CoV-1 NSP1和SARS-CoV-2 NSP1与DNA聚合酶α-引发酶的结合亲和力。我们的全原子SMD和粗粒度US模拟一致表明，与SARS-CoV-1 NSP1相比，SARS-CoV-2 NSP1对DNA聚合酶α-引发酶表现出更强的亲和力，这意味着SARS-CoV-2在阻碍DNA合成的DNA复制方面比SARS-CoV-1构成更大的风险。通过对这些复合物内相互作用能的能量分解分析，我们确定静电相互作用是观察到的结合亲和力差异的主要贡献因素。我们发现，SARS1 NSP1-DNA聚合酶α-引发酶中Asp33与Arg616之间的氢键，以及SARS2 NSP1-DNA聚合酶α-引发酶中Asp33与Arg616和Lys655之间的氢键，对于SARS-CoV-1 NSP1和SARS-CoV-2 NSP1与DNA聚合酶α-引发酶的相互作用至关重要。与SARS-CoV-1 NSP1相比，SARS-CoV-2 NSP1中的Asp33表现出更高的溶解度和稳定性，增强了其与DNA聚合酶α-引发酶的结合。这一发现为旨在抑制这些实体之间相互作用的创新策略奠定了基础，为针对新冠肺炎的治疗干预提供了有希望的途径。我们还使用MM-PBSA方法估计了DNA与DNA聚合酶α-引发酶、SARS1 NSP1-DNA聚合酶α-引发酶和SARS2 NSP1-DNA聚合酶α-引发酶的结合自由能。结果显示顺序为：DNA聚合酶α-引发酶-DNA < SARS1 NSP1-DNA聚合酶α-引发酶-DNA < SARS2 NSP1-DNA聚合酶α-引发酶-DNA，表明SARS-CoV-1 NSP1和SARS-CoV-2 NSP1均降低了DNA与DNA聚合酶α-引发酶的结合，提示DNA合成受损。
