Materials Science Division, Argonne National Laboratory, Argonne, Illinois, USA.
Biophys J. 2013 Sep 3;105(5):1227-35. doi: 10.1016/j.bpj.2013.07.029.
The formation of human islet amyloid polypeptide (hIAPP) is implicated in the loss of pancreatic β-cells in type II diabetes. Rat amylin, which differs from human amylin at six residues, does not lead to formation of amyloid fibrils. Pramlintide is a synthetic analog of human amylin that shares three proline substitutions with rat amylin. Pramlintide has a much smaller propensity to form amyloid aggregates and has been widely prescribed in amylin replacement treatment. It is known that the three prolines attenuate β-sheet formation. However, the detailed effects of these proline substitutions on full-length hIAPP remain poorly understood. In this work, we use molecular simulations and bias-exchange metadynamics to investigate the effect of proline substitutions on the conformation of the hIAPP monomer. Our results demonstrate that hIAPP can adopt various β-sheet conformations, some of which have been reported in experiments. The proline substitutions perturb the formation of long β-sheets and reduce their stability. More importantly, we find that all three proline substitutions of pramlintide are required to inhibit β conformations and stabilize the α-helical conformation. Fewer substitutions do not have a significant inhibiting effect.
人胰岛淀粉样多肽（hIAPP）的形成与 II 型糖尿病中胰岛β细胞的丧失有关。与人类淀粉样肽在六个残基处不同的大鼠淀粉样肽不会导致淀粉样纤维的形成。普兰林肽是人类淀粉样肽的合成类似物，与大鼠淀粉样肽共有三个脯氨酸取代。普兰林肽形成淀粉样聚集的倾向要小得多，并且已广泛用于淀粉样肽替代治疗。已知这三个脯氨酸可减弱β-折叠的形成。但是，这些脯氨酸取代对全长 hIAPP 的详细影响仍知之甚少。在这项工作中，我们使用分子模拟和偏置交换元动力学来研究脯氨酸取代对 hIAPP 单体构象的影响。我们的结果表明，hIAPP 可以采用各种β-折叠构象，其中一些已在实验中报道过。脯氨酸取代会破坏长β-折叠的形成并降低其稳定性。更重要的是，我们发现普兰林肽的三个脯氨酸取代均需要抑制β构象并稳定α-螺旋构象。较少的取代没有明显的抑制作用。
