| Summary: | 碩士 === 國立臺北科技大學 === 生物科技研究所 === 97 === The LYQLEN and VEALYL peptides from the A chain (residues 13-18) and B chain (residues 12-17) of insulin has been shown to form amyloid-like fibrils. Recently, the atomic structures of the LYQLEN and VEALYL oligomers have been determined by x-ray microcrystallography and reveal a dry, tightly self-complementing structure between the neighboringβ-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 LYQLEN and VEALYL peptides with various sizes and their single glycine replacement mutations. The results of our single-layer models showed that the structural stability of the LYQLEN and VEALYL oligomers increases significantly with increasing the number ofβ-strands. We further suggested that the minimal nucleus seed for LYQLEN and VEALYL fibril formation could be as small as trimer or tetramer. Our results also revealed that the hydrophobic interaction between glutamate and tyrosine plays an important role in stabilizing the adjacentβ-strands within the same layer for LYQLEN and VEALYL oligomers. For the case VEALYL oligomers, the hydrophobic steric zipper formed via the side chains of V1, A3, L4, Y5, and L6 plays a critical role in holding the two opposingβ-sheets together. Mutation simulations showed that single glycine substitution at V1, A3, L4, Y5 and L6 directly destroyed the steric zipper, leading to the destabilization of the VEALYL oligomers. For the case of LYQLEN oligomers, the steric zipper via the side chains of L1, Q3, L4, and N6 associates two neighbouringβ-sheet layers together. Mutation simulations showed that the replacement of Y2 or E5 by a single glycine residue exhibits strong destabilizing effects on the adjacentβ-strands within the same layer; whereas single glycine substitution at L1, Q3, L4, and N6 directly disrupts the steric zipper between the two neighbouringβ-sheet layers, resulting in the destabilization of the entire LYQLEN oligomers. The results of this study provide detailed atomistic insights into the factors stabilizing the LYQLEN and VEALYL oligomers and the aggregation behaviour of these two peptides. It may also provide helpful information for designing new or modified inhibitor able to prevent the fibrillization of the insulin protein.
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