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人淀粉样胰岛多肽在磷脂双层膜表面吸附和取向的分子动力学模拟研究
【作者】 贾彦；
【导师】 韦广红；
【作者基本信息】 复旦大学 ， 凝聚态物理， 2013， 硕士
【摘要】 蛋白质错误折叠和聚集会导致诸如阿尔兹海默症和二型糖尿病等严重的慢性疾病。人胰岛淀粉样多肽(human islet amyloid polypeptide-hIAPP或Amylin)是在二型糖尿病患者的胰腺中发现的淀粉样沉淀的主要成分。越来越多的实验数据显示人β细胞膜毒性与能够加快聚集的hIAPP和细胞膜相互作用密切相关。但是由于实验方法在空间分辨和时间分辨上的局限性,对于hIAPP与细胞膜相互作用过程,尤其是相互作用的最初阶段并不清楚,分子动力学模拟可以在原子尺度上给出二者相互作用的详细过程,从而弥补实验方法的不足。本文中,作为了解hIAPP和膜相互作用的第一步,我们使用全原子动力学(MD)模拟从原子水平研究了hIAPP和膜相互作用的最初阶段,包括吸附、取向及hIAPP单体的构象变化等。我们发现hIAPP单体很快的吸附到磷脂双分子层上,对于带负电的POPG磷脂双分子膜,hIAPP的N端最先吸附是由于强烈的静电相互作用,尤其是带正电的氨基酸K1和R11起到了很大的作用。两性的POPC膜,则N端和C端基本等几率优先吸附；hIAPP基本平行吸附到膜表面,氨基酸7-22保持稳定的α螺旋,这和过去的实验结果一致；特别的是,两种膜体系有两个不同的吸附面,POPG体系是氨基酸R11,F15和S19朝向膜,POPC体系是氨基酸T9,N14和H18。
【Abstract】 Protein misfolding and aggregation cause serious degenerative diseases such as Alzheimer’s and type2diabetes. Human islet amyloid polypeptide (hIAPP) is the major component of amyloid deposits found in the pancreas of type II diabetic patients. Increasing evidence suggests that β-cell death is related to the interaction of hIAPP with cellular membrane which accelerates peptide aggregation. However, the molecular mechanism of interaction and subsequent membrane perturbation at atomic level remains poorly understood. In this study, as a first step towards understanding the membrane-mediated hIAPP aggregation, we investigate the atomic details of the initial step of hIAPP-membrane interaction, including the adsorption, orientation, and conformation of hIAPP monomer at an anionic lipid bilayer by performing all-atom molecular dynamics (MD) simulations. We found that hIAPP monomer is quickly adsorbed to bilayer surface. For the POPG system, the adsorption is initiated from the N-terminal residues driven by strong electrostatic interactions of the positively-charged residues Kl and R11with negatively-charged lipid headgroups. For the POPC system, N-terminal and C-terminal can both first adsorb to the POPC. hIAPP binds parallel to lipid bilayer surface as a stable helix through residues7-22, consistent with previous experimental study. Remarkably, both systems lead to the same binding orientation separately. Residues R11, F15and S19oriented towards membrane for the POPG system, while residues T9, N14and H18towards membrane in the POPC system.