Department of Chemistry & Biochemistry, University of Oklahoma, Norman, Oklahoma 73019, United States.
J Chem Theory Comput. 2020 Aug 11;16(8):5358-5368. doi: 10.1021/acs.jctc.0c00523. Epub 2020 Jul 28.
Motivated by the role that amylin aggregates play in type-II diabetes, we compare the stability of regular amylin fibrils with the stability of fibrils where l-amino acid chains are replaced by d-retro inverso (DRI) amylin, that is, peptides where the sequence of amino acids is reversed, and at the same time, the l-amino acids are replaced by their mirror images. Our molecular dynamics simulations show that despite leading to only a marginal difference in the fibril structure and stability, aggregating DRI-amylin peptides have different patterns of contacts and hydrogen bonding. Because of these differences, DRI-amylin, when interacting with regular (l) amylin, alters the elongation process and lowers the stability of hybrid amylin fibrils. Our results not only suggest the potential use of DRI-amylin as an inhibitor of amylin fibril formation but also point to the possibility of using the insertion of DRI proteins in l-assemblies as a way to probe the role of certain kinds of hydrogen bonds in supramolecular assemblies or aggregates.
受胰岛淀粉样多肽在 II 型糖尿病中所起作用的启发，我们比较了普通胰岛淀粉样多肽原纤维的稳定性与由 L-氨基酸链取代 D-型氨基酸（DRI）的胰岛淀粉样多肽原纤维的稳定性，即序列被反转的肽，同时 L-氨基酸被其镜像取代。我们的分子动力学模拟表明，尽管 DRI-胰岛淀粉样多肽在原纤维结构和稳定性方面只导致了微小的差异，但聚集的 DRI-胰岛淀粉样多肽具有不同的接触和氢键模式。由于这些差异，DRI-胰岛淀粉样多肽与普通（L）胰岛淀粉样多肽相互作用时，会改变其延伸过程并降低杂交胰岛淀粉样多肽原纤维的稳定性。我们的研究结果不仅表明 DRI-胰岛淀粉样多肽可能作为胰岛淀粉样多肽原纤维形成的抑制剂，还指出在 L-聚集体中插入 DRI 蛋白作为一种方法来研究特定种类氢键在超分子组装体或聚集体中的作用的可能性。
