Department of Biosciences, University of Salzburg, Hellbrunnerstrasse 34, 5020, Salzburg, Austria.
School of Chemistry, College of Science, University of Tehran, P.O. Box 14155-6619, Tehran, Iran.
Chembiochem. 2022 Feb 16;23(4):e202100604. doi: 10.1002/cbic.202100604. Epub 2021 Dec 16.
The β-hairpin is a structural element of native proteins, but it is also a useful artificial scaffold for finding lead compounds to convert into peptidomimetics or non-peptide structures for drug discovery. Since linear peptides are synthetically more easily accessible than cyclic ones, but are structurally less well-defined, we propose XWXWXpPXK(/R)X(R) as an acyclic but still rigid β-hairpin scaffold that is robust enough to accommodate different types of side chains, regardless of the secondary-structure propensity of the X residues. The high conformational stability of the scaffold results from tight contacts between cross-strand cationic and aromatic side chains, combined with the strong tendency of the d-Pro-l-Pro dipeptide to induce a type II' β-turn. To demonstrate the robustness of the scaffold, we elucidated the NMR structures and performed molecular dynamics (MD) simulations of a series of peptides displaying mainly non-β-branched, poorly β-sheet-prone residues at the X positions. Both the NMR and MD data confirm that our acyclic β-hairpin scaffold is highly versatile as regards the amino-acid composition of the β-sheet face opposite to the cationic-aromatic one.
β-发夹是天然蛋白质的结构元件，但它也是一个有用的人工支架，可用于寻找先导化合物，将其转化为肽模拟物或非肽结构，以用于药物发现。由于线性肽比环状肽在合成上更容易获得，但结构上的定义较差，因此我们提出了 XWXWXpPXK(/R)X(R) 作为一种无环但仍然刚性的 β-发夹支架，它足够坚固，可以容纳不同类型的侧链，而不受 X 残基的二级结构倾向的影响。支架的高构象稳定性源于跨链阳离子和芳香族侧链之间的紧密接触，以及 d-Pro-l-Pro 二肽诱导 II'β-转角的强烈趋势。为了证明支架的坚固性，我们阐明了一系列肽的 NMR 结构，并进行了分子动力学 (MD) 模拟，这些肽在 X 位置主要显示非-β-支化、β-折叠倾向差的残基。NMR 和 MD 数据均证实，我们的无环 β-发夹支架在与阳离子-芳香族相对的 β-面的氨基酸组成方面具有高度的多功能性。
