Wu Chun, Lei Hongxing, Wang Zhixiang, Zhang Wei, Duan Yong
Genome Center and Department of Applied Science, University of California, Davis, California 95616, USA.
Biophys J. 2006 Nov 15;91(10):3664-72. doi: 10.1529/biophysj.106.081877. Epub 2006 Aug 25.
Amyloid-associated diseases affect millions of people worldwide. Phenol red exhibits modest inhibition toward fibril formation of human Islet amyloid polypeptide (hIAPP) and its toxicity, which is associated with type II diabetes mellitus. However, the molecular level mechanisms of interactions remain elusive. The binding of phenol red molecules to the protofibrils of an amyloidogenic fragment (NFGAIL) of hIAPP has been investigated by molecular dynamics simulations with explicit solvent. The phenol red molecules were observed to bind primarily along either beta-sheet stacking or beta-strand directions. Through its three aromatic rings, the phenol red molecule preferentially interacted with the hydrophobic side chains of Phe, Leu, and Ile; and the polar sulfone and hydroxyl groups were mainly exposed in solvent. Thus, phenol red improves the solubility of the early protofibrils and represses further growth. Interestingly, there was no obvious preference toward the aromatic Phe residue in comparison to the hydrophobic Leu or Ile residues. The lack of binding along the hydrogen bond direction indicates that phenol red does not directly block the beta-sheet extension. Further free energy analysis suggested that a phenol red analog may potentially improve the binding affinity.
淀粉样蛋白相关疾病在全球影响着数百万人。酚红对人胰岛淀粉样多肽（hIAPP）的纤维形成及其毒性表现出适度的抑制作用，这与II型糖尿病有关。然而，相互作用的分子水平机制仍然难以捉摸。通过含显式溶剂的分子动力学模拟研究了酚红分子与hIAPP淀粉样生成片段（NFGAIL）原纤维的结合。观察到酚红分子主要沿β-折叠堆积或β-链方向结合。通过其三个芳香环，酚红分子优先与苯丙氨酸、亮氨酸和异亮氨酸的疏水侧链相互作用；极性砜基和羟基主要暴露在溶剂中。因此，酚红提高了早期原纤维的溶解度并抑制了进一步生长。有趣的是，与疏水的亮氨酸或异亮氨酸残基相比，对芳香族苯丙氨酸残基没有明显的偏好。沿氢键方向缺乏结合表明酚红不会直接阻止β-折叠的延伸。进一步的自由能分析表明，酚红类似物可能会提高结合亲和力。
