HIV-1 gp120的构象控制机制

HIV-1病毒在进入宿主细胞过程中,其膜糖蛋白gp120的一系列构象重排与病毒的入侵以及免疫逃避密切相关。然而，全长gp120分子在孤立和病毒轴环境中究竟采取哪些构象状态？引起其构象变化的因素及其控制机制是否相同等关键问题尚不清楚。本项目拟在前期工作的基础上，构建不包含环区的、以及全长的、处于受体结合前后两种构象状态的gp120结构模型和病毒轴模型，通过分子动力学模拟和自由能全景图谱计算，归类、分析溶液环境中孤立gp120以及病毒轴中gp120的各种平衡构象状态及其之间的转换能力；分析V1/V2、V3环以及gp41相互作用对gp120构象稳定及转换的影响。本研究将获得病毒轴环境中全长gp120分子的构象多样性信息，并探明维持gp120构象平衡以及导致gp120构象变化的结构因素。研究结果将弥补晶体学和物理化学研究的不足，有助于揭示gp120的构象控制机制和HIV-1的免疫逃避机制。

During the process of HIV-1 virus entry into the host cells, the viral envelope glycoprotein gp120 undergoes a series of conformational rearrangements that are proposed to be linked to the virus invasion and immune evasion. However, how many conformational states can the full-length gp120 assume in its isolated form or in the viral spike environment? Do the factors that cause conformational changes and their underlying mechanisms of control differ between the isolated gp120 and spike gp120? These two key questions have remained elusive. This project will construct the loop-truncated and full-length structural models for both the isolated and functional viral spike gp120, either in the unliganded or in the CD4-bound states. These models will be subjected to extensive molecular dynamics simulations followed by calculations and analyses of free energy landscapes of these protein-solvent systems. Our aims are to (i) cluster a variety of potential gp120 conformational states that co-exist in equilibrium and to analyze the conformational transition ability between them; (ii) analyze the effects of the V1/V2, V3 variable loops and gp41 interaction on the stability of distinct gp120 conformational states and on the transition between them. The expected results are that we would obtain the information about the conformational diversity of the full-length gp120 molecule in the functional viral spike environment, and would find out the structural factors capable of maintaining the conformational equilibrium or causing conformational transition between these equilibrium states. The results of this project will complement the data derived from the X-ray crystallographic and physicochemical studies, thus facilitating the understanding of the conformational control mechanism of gp120 and the mechanism of the immune evasion of HIV-1.