Graduate Institute of Biotechnology, National Taipei University of Technology, Taipei, Taiwan.
Biopolymers. 2010;94(3):269-78. doi: 10.1002/bip.21322.
The VEALYL peptide from B chain (residues 12-17) of insulin has been shown to form amyloid-like fibrils. Recently, the atomic structure of the VEALYL oligomer has been determined by X-ray microcrystallography and reveals a dry, tightly self-complementing structure between the neighboring beta-sheet layers, termed as "steric zipper." In this study, several molecular dynamics simulations with all-atom explicit water were conducted to investigate the structural stability and aggregation behavior of the VEALYL peptide with various sizes and its single glycine replacement mutations. The results of our single-layer models showed that the structural stability of the VEALYL oligomers increases significantly with increasing the number of beta-strands. We further suggested that the minimal nucleus seed for VEALYL fibril formation could be as small as three or four peptides. Our results also revealed that the hydrophobic interaction between E2 and Y5 plays an important role in stabilizing the adjacent beta-strands within the same layer, whereas the hydrophobic steric zipper formed via the side chains of V1, A3, L4, Y5, and L6 locks the two neighboring beta-sheet layers together. Mutation simulations showed that the substitution of a single glycine residue directly disrupts this steric zipper, resulting in the destabilization of the VEALYL oligomers. This study provides the atomic insights into understanding the aggregation behavior of the VEALYL peptide. It may also be helpful for designing new or modified capping peptides able to break the driving force for aggregation and to prevent the fibril formation of the VEALYL peptide and the insulin protein.
VEALYL 肽来源于胰岛素 B 链（残基 12-17），已被证明能形成淀粉样纤维。最近，VEALYL 低聚物的原子结构已通过 X 射线微晶体学确定，揭示了相邻 β-折叠层之间的干燥、紧密自互补结构，称为“空间拉链”。在这项研究中，我们进行了多次带有全原子显式水的分子动力学模拟，以研究不同大小的 VEALYL 肽及其单个甘氨酸取代突变体的结构稳定性和聚集行为。我们单层模型的结果表明，VEALYL 低聚物的结构稳定性随着 β-链数量的增加而显著提高。我们进一步提出，VEALYL 纤维形成的最小核种子可能小至三四个肽。我们的结果还表明，E2 和 Y5 之间的疏水相互作用在稳定同一层内相邻 β-链方面起着重要作用，而通过 V1、A3、L4、Y5 和 L6 的侧链形成的疏水力拉链将两个相邻的 β-折叠层锁定在一起。突变模拟表明，单个甘氨酸残基的取代直接破坏了这种空间拉链，导致 VEALYL 低聚物的不稳定性。这项研究提供了原子水平上对 VEALYL 肽聚集行为的理解。它也可能有助于设计新的或修饰的盖帽肽，以打破聚集的驱动力，并防止 VEALYL 肽和胰岛素蛋白的纤维形成。
