【作者】 何沛思；

【导师】 魏冬青；

【作者基本信息】 上海交通大学 ， 生物医学工程， 2012， 硕士

【摘要】 流行性感冒(简称流感)是由流感病毒引起的急性呼吸道感染,每次大爆发在人群中有着显著的发病率和一定的致死率。乙型流感病毒引起的疾病占流感病毒的50%,会呈现周期性的大爆发,感染对象主要是老人、小孩以及孕妇等免疫力相对较低的人群。所以乙型流感病毒的研究非常重要。乙型流感病毒质子通道蛋白BM2是由四个单次跨膜蛋白单体组成的同源四聚体,BM2在病毒复制的过程中起了非常关键的作用。其跨膜段的HXXXW基序是M2蛋白形式其质子传递的选择性和门控性的关键氨基酸。阻断BM2的质子通道活性,将能在病毒感染早期有效控制病毒的复制,所以BM2有希望成为抗乙型流感病毒的药物靶点,所以对其的研究将成为对抗流感病毒研制的理论基础。分子动力学模拟是建立在牛顿力学的基础上的一种分子模拟方法,通过求解牛顿力学方程可以获得一些体系随时间变化的热力学和动力学性质。分子动力学模拟是一种对膜蛋白这种通过实验手段研究比较困难的生物体系的有效的研究方法。在生物体系中较常用的力场中,本文使用GROMACS4.5软件,选择了GROMOS87力场以及OPLS力场分别对BM2蛋白进行了25ns的分子动力学模拟。通过模拟结果的对比,可以反映两个力场在膜蛋白模拟的应用上的差异和优劣,OPLS力场更加精细的描绘了蛋白的运动情况,相对更加精细的反映水分子的分布情况。希望对分子动力学模拟的力场选择方案提出了一定的建议。OPLS力场更加精细的描绘了通道半径的变化情况,以及更加精细的反映水分子的分布情况。BM2的跨膜段PHE5和TRP23的侧链将通道堵住,这些氨基酸附近的通道半径都小于水分子半径,分别起到了N端和C端的门的作用。水分子通过PHE5、HIS19和TRP23需要越过更高的能垒。更多还原

【Abstract】 Flu is caused by influenza virus inflection, which accompanies a significant level of morbidity and mortality. Influenza virus B is an important constituent of human seasonal flu that accounts for about 50% of all influenza disease in recent years, which causes pandemic disease periodically. Due to willing to control actions in the event of a pandemic, it is very important to do some research on influenza virus B. BM2, the proton channel of influenza virus B, is a single-span membrane protein, which is a homotetramer in its native state. BM2 is responsible for acidizing virus and releasing the vRNA. The HXXXW sequence motif in the transmembrane domain is essential for pH sensing and channel gating.Molecular dynamics simulations is a method establishing a molecular simulation on the basis of Newtonian mechanics. By solving the Newtonian mechanical equations can obtain thermodynamic and kinetic properties changing over time. We simulated BM2 for 25ns respectively under GROMOS87 and OPLS force field by using GROMACS 4.5. By the comparation of the results, we noticed that there are some similarity but also much more discrepancy in the application of the two force field. OPLS force field has better performance in simulation, because of the elavorate characteristcs of protein movements and water distribution. The side chain of PHE5 and TRP23 in BM2 transmembrane block the channel, and near these amino acids, the channel radius is smaller than the radius of the water molecules. PHE5 and TRP23 play the role of gate respectively, for the N-terminal and C-terminal . Potentials of mean force for the water along the z axis of the BM2 pore has shown that it has to pass over a much higher energy barrier, which proves the reason for water absence shown by the water density figure.更多还原