Department of Chemistry Hunter College and the Graduate School, City University of New York , 695 Park Avenue, New York, New York 10065, United States.
J Phys Chem B. 2014 Mar 27;118(12):3326-34. doi: 10.1021/jp501890p. Epub 2014 Mar 17.
We present ONIOM calculations using density functional theory (DFT) as the high and AM1 as the medium level that explore the abilities of different hexapeptide sequences to terminate the growth of a model for the tau-amyloid implicated in Alzheimer's disease. We delineate and explore several design principles (H-bonding in the side chains, using antiparallel interactions on the growing edge of a parallel sheet, using all-d residues to form rippled interactions at the edge of the sheet, and replacing the H-bond donor N-H's that inhibit further growth) that can be used individually and in combination to design such peptides that will have a greater affinity for binding to the parallel β-sheet of acetyl-VQIVYK-NHCH3 than the natural sequence and will prevent another strand from binding to the sheet, thus providing a cap to the growing sheet that arrests further growth. We found peptides in which the Q is replaced by an acetyllysine (aK) residue to be particularly promising candidates, particularly if the reverse sequence (KYVIaKV) is used to form an antiparallel interaction with the sheet.
我们使用密度泛函理论（DFT）作为高精度方法，用 AM1 方法作为中精度方法，进行了 ONIOM 计算，以探索不同六肽序列终止与阿尔茨海默病相关的 tau-淀粉样蛋白模型生长的能力。我们描述并探索了几种设计原则（侧链中的氢键、在平行片的生长边缘使用反平行相互作用、使用全 d 残基在片的边缘形成波纹相互作用、以及取代抑制进一步生长的 N-H 供体氢键），这些原则可以单独使用或组合使用，设计出与天然序列相比对乙酰-VQIVYK-NHCH3 平行 β-片具有更高亲和力的肽，并且防止另一个肽链与片结合，从而为生长片提供一个盖帽，阻止进一步生长。我们发现，用乙酰赖氨酸（aK）取代 Q 的肽是特别有前途的候选物，特别是如果使用相反的序列（KYVIaKV）与片形成反平行相互作用。
