Liu Yuewu, Zou Xiufen
School of Mathematics and Statistics, Wuhan University, Computational Science Hubei Key Laboratory, Wuhan University, Wuhan, China.
College of Science, Hunan Agricultural University, Hunan, China.
PLoS Comput Biol. 2017 Sep 18;13(9):e1005733. doi: 10.1371/journal.pcbi.1005733. eCollection 2017 Sep.
Gag, as the major structural protein of HIV-1, is necessary for the assembly of the HIV-1 sphere shell. An in-depth understanding of its trafficking and polymerization is important for gaining further insights into the mechanisms of HIV-1 replication and the design of antiviral drugs. We developed a mathematical model to simulate two biophysical processes, specifically Gag monomer and dimer transport in the cytoplasm and the polymerization of monomers to form a hexamer underneath the plasma membrane. Using experimental data, an optimization approach was utilized to identify the model parameters, and the identifiability and sensitivity of these parameters were then analyzed. Using our model, we analyzed the weight of the pathways involved in the polymerization reactions and concluded that the predominant pathways for the formation of a hexamer might be the polymerization of two monomers to form a dimer, the polymerization of a dimer and a monomer to form a trimer, and the polymerization of two trimers to form a hexamer. We then deduced that the dimer and trimer intermediates might be crucial in hexamer formation. We also explored four theoretical combined methods for Gag suppression, and hypothesized that the N-terminal glycine residue of the MA domain of Gag might be a promising drug target. This work serves as a guide for future theoretical and experimental efforts aiming to understand HIV-1 Gag trafficking and polymerization, and might help accelerate the efficiency of anti-AIDS drug design.
作为HIV-1的主要结构蛋白，Gag对于HIV-1病毒球体外壳的组装是必需的。深入了解其运输和聚合过程对于进一步洞察HIV-1复制机制以及抗病毒药物设计具有重要意义。我们建立了一个数学模型来模拟两个生物物理过程，具体为细胞质中Gag单体和二聚体的运输以及单体在质膜下聚合成六聚体的过程。利用实验数据，采用优化方法确定模型参数，随后分析这些参数的可识别性和敏感性。通过我们的模型，我们分析了聚合反应中各途径的权重，并得出形成六聚体的主要途径可能是两个单体聚合成二聚体、一个二聚体和一个单体聚合成三聚体以及两个三聚体聚合成六聚体。然后我们推断二聚体和三聚体中间体可能在六聚体形成过程中至关重要。我们还探索了四种Gag抑制的理论组合方法，并推测Gag的MA结构域的N端甘氨酸残基可能是一个有前景的药物靶点。这项工作为未来旨在理解HIV-1 Gag运输和聚合的理论和实验研究提供了指导，并可能有助于提高抗艾滋病药物设计的效率。
