Laboratory of Chemical Physics, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, Maryland, USA.
Biophys J. 2011 Jun 22;100(12):3035-44. doi: 10.1016/j.bpj.2011.05.025.
We report Monte Carlo simulations of the initial stages of self-assembly of the HIV-1 capsid protein (CA), using a coarse-grained representation that mimics the CA backbone structure and intermolecular contacts observed experimentally. A simple representation of N-terminal domain/N-terminal domain and N-terminal domain/C-terminal domain interactions, coupled with the correct protein shape, is sufficient to drive formation of an ordered lattice with the correct hexagonal symmetry in two dimensions. We derive an approximate concentration/temperature phase diagram for lattice formation, and we investigate the pathway by which the lattice develops from initially separated CA dimers. Within this model, lattice formation occurs in two stages: 1), condensation of CA dimers into disordered clusters; and 2), nucleation of the lattice by the appearance of one hexamer unit within a cluster. Trimers of CA dimers are important early intermediates, and pentamers are metastable within clusters. Introduction of a preformed hexamer at the beginning of a Monte Carlo run does not directly seed lattice formation, but does facilitate the formation of large clusters. We discuss possible connections between these simulations and experimental observations concerning CA assembly within HIV-1 and in vitro.
我们报告了 HIV-1 衣壳蛋白 (CA) 自组装初始阶段的蒙特卡罗模拟，使用了一种粗粒度的表示形式，模拟了实验中观察到的 CA 骨架结构和分子间相互作用。简单表示 N 端结构域/N 端结构域和 N 端结构域/C 端结构域相互作用，再加上正确的蛋白质形状，足以在二维空间中驱动具有正确六边形对称性的有序晶格的形成。我们得出了一个近似的浓度/温度相图，用于晶格形成，并研究了晶格从最初分离的 CA 二聚体发展的途径。在这个模型中，晶格的形成分两个阶段进行：1），CA 二聚体凝聚成无序的聚集体；2），通过在聚集体内出现一个六聚体单元，晶格的成核。三聚体的 CA 二聚体是重要的早期中间体，五聚体在聚集体内是亚稳定的。在蒙特卡罗运行开始时引入预先形成的六聚体不会直接引发晶格形成，但会促进大聚集体的形成。我们讨论了这些模拟与关于 HIV-1 内部和体外 CA 组装的实验观察之间的可能联系。
