Abstract: The human chemokine receptor CCR5 is a major coreceptor for human immunodeficiency virus type-1 strains entry into cell. Studies of site directed mutagenesis and chimeric receptors have indicated that the N terminus region of CCR5 is important for chemokines binding, viral fusion, and entry. Three-dimensional models of CCR5 were built by using homology modeling approach, a 1ns high temperature (1000K) molecular dynamics simulation and a subsequent 200ps normal temperature molecular dynamics simulation were performed for CCR5 extracellular domain. The results indicate that the extracellular segments of CCR5 form a well-packet globular domain, the disulfide bond Cys20-Cys269 is essential in keeping conformational integrity of extracellular domain and controlling specific orientation of N terminus region that involved in ligands and HIV binding. Also, this disulfide bond enhances the conformational flexibility of N terminus, makes it locate at the top surface of extracellular domain, and affords N terminus more opportunities to project into the outer space of this domain. Integration these results with available experimental data, a two-step gp120-CCR5 binding mechanism is proposed.

Key words: CCR5, molecular dynamics simulation, N terminus region, disulfide bond, HIV

摘要： 人类化学趋化因子受体CCR5是HIV-1病毒进入人体细胞的主要辅助受体。实验表明，CCR5分子的N末端区域对化学趋化因子结合以及HIV病毒入侵起关键作用。用同源模建的方法构建CCR5结构模型，并对该模型的胞外结构域进行了1ns高温分子动力学和200ps常温分子动力学模拟。结果表明，CCR5的胞外结构域整体上表现为一个包装紧密的球形构象，二硫键Cys20-Cys269对这一构象的形成以及N末端区域的空间取向起关键作用，同时，二硫键的存在使N末端1-19区域定位在胞外结构域的顶部，并增加N末端构象柔性，使其有机会伸展到胞外空间去。根据这一结果和现有的实验证据，提出了HIV-CCR5两步结合机制。

关键词: CCR5, 分子动力学模拟, N末端区域, 二硫键, HIV