膜蛋白跨膜区相互作用的分子动力学模拟研究
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摘要
分化抗原36(CD36)，血小板膜糖蛋白(Glycoprotein，GP)，DNAX激活蛋白12(DAP12)都是本实验室研究的膜蛋白，它们在细胞膜上具有多种功能，作用十分关键。课题组使用多种生化实验的方法来研究这些其跨膜区相互作用，已经得到了很多有重要意义的实验数据。发现其跨膜区部分能通过相互作用在膜内发生寡聚现象，调控了膜内外的信号传导。因此，使用分子动力学模拟方法来进一步研究跨膜螺旋如何在双层膜中自组装，并形成具有生物功能的寡聚复合物。
首先，使用全原子模拟的方法研究了CD36跨膜区1野生型和突变型G16I的装配特性。发现G8对装配影响非常低；G12对装配影响略高于G8；G16和A20还有G23等3组氨基酸之间有强烈相互作用，对二聚装配有关键作用。其突变体G16I不能形成稳定二聚体。
接着，通过全原子模拟方法观察了GPIB-IX复合物跨膜区的装配过程。发现复合物跨膜区中的几个极性氨基酸的确主导了的寡聚。IB通过靠近N端的Y492，C端的A502和S503来与IBβN端的Q129和C端的H139装配，而IX通过靠近N端的D135和C端的多个疏水氨基酸来与IBβN端的Q129和C端的疏水氨基酸装配。
最后，多次粗粒化模拟了DAP12跨膜区的二聚装配过程，获得了量化的结果。发现在交叉角分布图中，V42野生型的左手装配出现的次数高于右手装配，而且2个跨膜螺旋之间的接触区域是很集中的，在随后的全原子模拟结果中也证明了左手装配是稳定的装配方式。非破坏性突变的确能够加强二聚的强度，交叉角分布图和螺旋接触图都与V42非常相似。破坏性突变不能产生稳定的装配，其交叉角分布图上左手装配的数量大大降低了，在螺旋接触图上它们产生了与V42完全不同的装配方式。
使用全原子模拟和粗粒化模拟2种分子动力学模拟方法研究了跨膜区相互作用，获得了生化分子的结构信息，验证了生化实验结果，在氨基酸分子层面上解释其相互作用机制。并且预测了新的跨膜螺旋相互作用位点，指导未来的生化实验。
CD36, GP, DAP12were well researched in our lab, they aremultifunctional and play a vital role on the cell membrane. Our group has usedvarious biochemistry methods to study their transmembrane(TM) domaininteractions. We found that their TM domains could self-assemble intooligomerization and regulate signaling transmission. We used to study deeplyon how these TM domains interact with each other in the bilayer and integrateinto oligomer by molecular dynamics simulation.
First, atomatics simulation(AT-MD) was applied to study the features ofCD36TM1WT and its mutant G16I. We found that G8has little effect andG12has small effect on dimerizaton. G16, A20, G23pairs have stronginteraction driving the2TM helices into dimer. When G16was mutate into I,the2TM helice could not self-assemble into dimer.
Second, AT-MD was used to study the packing course of the GPIB-IXcomplex and found that several polar residues have dominant role in complexoligomerization. These residues are Y492, A502, S503of IB, Q129, H139ofIBβ, D135and some hydrophobic residues of IX.
Finally, coarse-grained simulation(CG-MD) was utilized to study DAP12.V42WT generate a bimodal packing dimer in crossing angle distribution, andthe left-handed(LH) packing had higher peek than right-handed(RH), LH andRH packing both shared same concentrated helix spatial contact area. Inadditional, LH packing was more stable dimer proved by the following AT-MD. All the non-disruptive mutants had similar crossing angle distributionsand helix spatial contacts with V42WT. In contrast, all the disruptive mutantscould not form stable dimmers and had fewer LH paking dimers than V42, andshow scattered helix spatial contacts area.
Overall,2kinds of molecular dynamics simulation method (AT-MD andCG-MD) were used to research TM domain interactions. The simulation datasverified the biochemical test results and explained the interaction mechanismsat the amino acid molecular level. Moreover, the datas could forecast somenew TM peptide interaction sites and guide future biochemical experiments.
首先，使用全原子模拟的方法研究了CD36跨膜区1野生型和突变型G16I的装配特性。发现G8对装配影响非常低；G12对装配影响略高于G8；G16和A20还有G23等3组氨基酸之间有强烈相互作用，对二聚装配有关键作用。其突变体G16I不能形成稳定二聚体。
接着，通过全原子模拟方法观察了GPIB-IX复合物跨膜区的装配过程。发现复合物跨膜区中的几个极性氨基酸的确主导了的寡聚。IB通过靠近N端的Y492，C端的A502和S503来与IBβN端的Q129和C端的H139装配，而IX通过靠近N端的D135和C端的多个疏水氨基酸来与IBβN端的Q129和C端的疏水氨基酸装配。
最后，多次粗粒化模拟了DAP12跨膜区的二聚装配过程，获得了量化的结果。发现在交叉角分布图中，V42野生型的左手装配出现的次数高于右手装配，而且2个跨膜螺旋之间的接触区域是很集中的，在随后的全原子模拟结果中也证明了左手装配是稳定的装配方式。非破坏性突变的确能够加强二聚的强度，交叉角分布图和螺旋接触图都与V42非常相似。破坏性突变不能产生稳定的装配，其交叉角分布图上左手装配的数量大大降低了，在螺旋接触图上它们产生了与V42完全不同的装配方式。
使用全原子模拟和粗粒化模拟2种分子动力学模拟方法研究了跨膜区相互作用，获得了生化分子的结构信息，验证了生化实验结果，在氨基酸分子层面上解释其相互作用机制。并且预测了新的跨膜螺旋相互作用位点，指导未来的生化实验。
CD36, GP, DAP12were well researched in our lab, they aremultifunctional and play a vital role on the cell membrane. Our group has usedvarious biochemistry methods to study their transmembrane(TM) domaininteractions. We found that their TM domains could self-assemble intooligomerization and regulate signaling transmission. We used to study deeplyon how these TM domains interact with each other in the bilayer and integrateinto oligomer by molecular dynamics simulation.
First, atomatics simulation(AT-MD) was applied to study the features ofCD36TM1WT and its mutant G16I. We found that G8has little effect andG12has small effect on dimerizaton. G16, A20, G23pairs have stronginteraction driving the2TM helices into dimer. When G16was mutate into I,the2TM helice could not self-assemble into dimer.
Second, AT-MD was used to study the packing course of the GPIB-IXcomplex and found that several polar residues have dominant role in complexoligomerization. These residues are Y492, A502, S503of IB, Q129, H139ofIBβ, D135and some hydrophobic residues of IX.
Finally, coarse-grained simulation(CG-MD) was utilized to study DAP12.V42WT generate a bimodal packing dimer in crossing angle distribution, andthe left-handed(LH) packing had higher peek than right-handed(RH), LH andRH packing both shared same concentrated helix spatial contact area. Inadditional, LH packing was more stable dimer proved by the following AT-MD. All the non-disruptive mutants had similar crossing angle distributionsand helix spatial contacts with V42WT. In contrast, all the disruptive mutantscould not form stable dimmers and had fewer LH paking dimers than V42, andshow scattered helix spatial contacts area.
Overall,2kinds of molecular dynamics simulation method (AT-MD andCG-MD) were used to research TM domain interactions. The simulation datasverified the biochemical test results and explained the interaction mechanismsat the amino acid molecular level. Moreover, the datas could forecast somenew TM peptide interaction sites and guide future biochemical experiments.
引文
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