信号传导蛋白Ras功能的分子机理的理论模拟与研究

Approximately 150 different guanine nucleotide-binding proteins are present in eukaryotic cells where they are responsible for various cellular processes. These include members of the Ras-related superfamily and others. The signal transduction processes involved in cell growth and differentiation are accomplished with the hydrolysis of guanosine triphosphate(GTP) in Ras. The GTP is hydrolyzed by Ras to yield guanosine diphosphate (GDP), with the Ras conformation switching from the "on" to "off" state. The resulted complex RasGDP can be reactivated again by exchanging the GDP for the second GTP. The cycling of GTP hydrolysis with Ras is critical for signal transduction in living cells. A malfunctions associated with constitutively active Ras can cause tumors. We will simulate and study the catalytic functions of Ras,including the molcular mechanism of GTP hydrolysis, the effect of Ras mutant on GTP hydrolysis and the relationship between the conformations of Ras protein and its activity, with using the combined quantum mechanics and molecular mechanics(QM/MM) simultion methods. The results of this project will give a clear explanation of the molecular mechanism of Ras functions at the atomistic level and provide a significant theoretical foundation for the drug design of anti-tumors.

真核细胞中大约150种包括鸟嘌呤核苷酸的蛋白参与了细胞中的各种过程，其中包括Ras家族蛋白。Ras蛋白能够控制细胞分裂与生长信号的传导，其功能与发生在Ras蛋白内的三磷酸鸟苷分子(GTP)的水解反应密切相关。Ras蛋白与GTP结合时处于活性状态，可以传导信号，当GTP发生水解反应后将转化为二磷酸鸟苷分子(GDP)使Ras蛋白质失活，关闭信号传导通路。Ras蛋白功能的失调将导致传导信号的不断放大,引起细胞恶性分裂增生,最终导致肿瘤的发生。我们将利用量子力学与分子动力学相结合(QM/MM)的方法模拟与研究Ras蛋白的功能,包括GTP分子水解的机理，Ras蛋白突变对其活性的影响，以及Ras蛋白构象活性与功能间的关系。研究Ras蛋白信号传导的分子机理为揭示肿瘤发病机理与设计抗肿瘤药物提供了重要的理论依据。

Ras 蛋白能够控制细胞分裂与生长信号的传导，其功能与发生在Ras 蛋白内的三磷酸鸟苷分子(GTP)的水解反应密切相关。Ras 蛋白功能的失调将导致传导信号的不断放大，引起细胞恶性分裂增生，最终导致肿瘤的发生。我们利用量子力学与分子动力学相结合(QM/MM)的方法以及传统的分子动力学模拟方法，研究了Ras中GTP分子的水解机理，模拟结果表明GTP在水分子的进攻发生水解生成GDP分子，并引起Ras蛋白的构象发生相应的变化。 Ras 蛋白的构象与其功能间具有密切的关系，发生水解反应后其构象将由活性构象变为非活性构象。由于其构象的变化具有较长的时间尺度，我们发展了描述Ras蛋白的粗粒化模型对其构象进行模拟。我们发展了快速的算法来对蛋白质进行粗粒化，该模型能够正确反应Ras蛋白二级结构的性质，通过参数化能够正确地描述其平衡态的构型。研究Ras 蛋白信号传导的分子机理为揭示肿瘤发病机理与设计抗肿瘤药物提供了重要的理论依据。