Faculty of Chemistry, Physical Chemistry I—Biophysical Chemistry, TU Dortmund University, Germany.
Biophys Chem. 2011 Jun;156(1):43-50. doi: 10.1016/j.bpc.2010.12.007. Epub 2010 Dec 31.
Conformational properties of the full-length human and rat islet amyloid polypeptide 1-37 (amyloidogenic hIAPP and non-amyloidogenic rIAPP, respectively) were studied at 310 and 330 K by MD simulations both for the cysteine (reduced IAPP) and cystine (oxidized IAPP) moieties. At all temperatures studied, IAPP does not adopt a well-defined conformation and is essentially random coil in solution, although transient helices appear forming along the peptide between residues 8 and 22, particularly in the reduced form. Above the water percolation transition (at 320 K), the reduced hIAPP moiety presents a considerably diminished helical content remaining unstructured, while the natural cystine moiety reaches a rather compact state, presenting a radius of gyration that is almost 10% smaller and characterized by intrapeptide H-bonds that form many β-bridges in the C-terminal region. This compact conformation presents a short end-to-end distance and seems to form through the formation of β-sheet conformations in the C-terminal region with a minimization of the Y/F distances in a two-step mechanism: the first step taking place when the Y37/F23 distance is ~1.1 nm, and subsequently Y37/F15 reaches its minimum of ~0.86 nm. rIAPP, which does not aggregate, also presents transient helical conformations. A particularly stable helix is located in proximity of the C-terminal region, starting from residues L27 and P28. Our MD simulations show that P28 in rIAPP influences the secondary structure of IAPP by stabilizing the peptide in helical conformations. When this helix is not present, the peptide presents bends or H-bonded turns at P28 that seem to inhibit the formation of the β-bridges seen in hIAPP. Conversely, hIAPP is highly disordered in the C-terminal region, presenting transient isolated β-strand conformations, particularly at higher temperatures and when the natural disulfide bond is present. Such conformational differences found in our simulations could be responsible for the different aggregational propensities of the two different homologues. In fact, the fragment 30-37, which is identical in both homologues, is known to aggregate in vitro, hence the overall sequence must be responsible for the amyloidogenicity of hIAPP. The increased helicity in rIAPP induced by the serine-to-proline variation at residue 28 seems to be a plausible inhibitor of its aggregation.
全长人胰岛素原淀粉样多肽 1-37（致淀粉样的 hIAPP 和非致淀粉样的 rIAPP）的构象性质在 310 和 330 K 下通过 MD 模拟进行了研究，分别针对半胱氨酸（还原型 IAPP）和胱氨酸（氧化型 IAPP）部分。在研究的所有温度下，IAPP 都没有采用明确的构象，在溶液中基本上是无规卷曲，尽管在 8 到 22 位残基之间的肽段中会出现短暂的螺旋，特别是在还原形式中。在水渗透转变（在 320 K 时）之上，还原的 hIAPP 部分的螺旋含量明显减少，保持无定形状态，而天然的胱氨酸部分则达到相当紧凑的状态，呈现出的回转半径小了近 10%，并且在 C 末端区域形成许多肽内氢键，形成许多β-桥。这种紧凑的构象具有较短的头尾距离，似乎是通过在 C 末端区域形成β-折叠构象形成的，通过最小化 Y/F 距离来实现，这是一个两步机制：第一步发生在 Y37/F23 距离约为 1.1nm 时，随后 Y37/F15 达到其最小值约 0.86nm。不聚集的 rIAPP 也具有短暂的螺旋构象。一个特别稳定的螺旋位于 C 末端区域附近，从残基 L27 和 P28 开始。我们的 MD 模拟表明，rIAPP 中的 P28 通过稳定螺旋构象来影响 IAPP 的二级结构。当不存在该螺旋时，肽在 P28 处呈现弯曲或氢键转弯，这似乎抑制了 hIAPP 中看到的β-桥的形成。相反，hIAPP 在 C 末端区域高度无序，呈现短暂的孤立β-链构象，特别是在较高温度和天然二硫键存在时。我们的模拟中发现的这种构象差异可能是两种不同同源物不同聚集倾向的原因。事实上，两个同源物中相同的 30-37 片段已知在体外聚集，因此整个序列必须对 hIAPP 的淀粉样特性负责。由残基 28 处丝氨酸到脯氨酸的变化引起的 rIAPP 螺旋度增加似乎是其聚集的合理抑制剂。
