Department of Materials Chemistry, Nagoya University , Nagoya 464-8603, Japan.
J Chem Inf Model. 2018 Feb 26;58(2):328-337. doi: 10.1021/acs.jcim.7b00471. Epub 2018 Jan 24.
Around 270 million individuals currently live with hepatitis B virus (HBV) infection. Heteroaryldihydropyrimidines (HAPs) are a family of antivirals that target the HBV capsid protein and induce aberrant self-assembly. The capsids formed resemble the native capsid structure but are unable to propagate the virus progeny because of a lack of RNA/DNA. Under normal conditions, self-assembly is initiated by the viral genome. The mode of action of HAPs, however, remains largely unknown. In this work, using molecular dynamics simulations, we attempted to understand the action of HAP by comparing the dynamics of capsid proteins with and without HAPs. We found that the inhibitor is more stable in higher oligomers. It retains its stability in the hexamer throughout 1 μs of simulation. Our results also show that the inhibitor might help in stabilizing the C-terminus, the HBc 149-183 arginine-rich domain of the capsid protein. The C-termini of dimers interact with each other, assisted by the HAP inhibitor. During capsid assembly, the termini are supposed to directly interact with the viral genome, thereby suggesting that the viral genome might work in a similar way to stabilize the capsid protein. Our results may help in understanding the underlying molecular mechanism of HBV capsid self-assembly, which should be crucial for exploring new drug targets and structure-based drug design.
目前，全球约有 2.7 亿人感染乙型肝炎病毒 (HBV)。杂芳基二氢嘧啶 (HAPs) 是一类针对 HBV 衣壳蛋白的抗病毒药物，可诱导异常的自组装。形成的衣壳类似于天然衣壳结构，但由于缺乏 RNA/DNA，无法复制病毒后代。在正常情况下，自组装是由病毒基因组启动的。然而，HAP 的作用机制在很大程度上仍不清楚。在这项工作中，我们使用分子动力学模拟，通过比较有和没有 HAP 的衣壳蛋白的动力学，试图了解 HAP 的作用。我们发现抑制剂在更高的低聚物中更稳定。在整个 1 μs 的模拟过程中，它在六聚体中保持稳定。我们的结果还表明，抑制剂可能有助于稳定衣壳蛋白的 C 末端，即 HBc 149-183 富含精氨酸的结构域。二聚体的 C 末端相互作用，由 HAP 抑制剂辅助。在衣壳组装过程中，末端应该直接与病毒基因组相互作用，这表明病毒基因组可能以类似的方式稳定衣壳蛋白。我们的结果可能有助于理解 HBV 衣壳自组装的潜在分子机制，这对于探索新的药物靶点和基于结构的药物设计至关重要。
