Sasselli I R, Moreira I P, Ulijn R V, Tuttle T
Department of Pure & Applied Chemistry, WestCHEM, University of Strathclyde, 295 Cathedral Street, Glasgow, G1 1XL, UK.
Org Biomol Chem. 2017 Aug 9;15(31):6541-6547. doi: 10.1039/c7ob01268c.
There is significant interest in the use of unmodified self-assembling peptides as building blocks for functional, supramolecular biomaterials. Recently, dynamic peptide libraries (DPLs) have been proposed to select self-assembling materials from dynamically exchanging mixtures of dipeptide inputs in the presence of a nonspecific protease enzyme, where peptide sequences are selected and amplified based on their self-assembling tendencies. It was shown that the results of the DPL of mixed sequences (e.g. starting from a mixture of dileucine, L, and diphenylalanine, F) did not give the same outcome as the separate L and F libraries (which give rise to the formation of F and L), implying that interactions between these sequences could disrupt the self-assembly. In this study, coarse grained molecular dynamics (CG-MD) simulations are used to understand the DPL results for F, L and mixed libraries. CG-MD simulations demonstrate that interactions between precursors can cause the low formation yield of hexapeptides in the mixtures of dipeptides and show that this ability to disrupt is influenced by the concentration of the different species in the DPL. The disrupting self-assembly effect between the species in the DPL is an important effect to take into account in dynamic combinatorial chemistry as it affects the possible discovery of new materials. This work shows that combined computational and experimental screening can be used complementarily and in combination providing a powerful means to discover new supramolecular peptide nanostructures.
将未修饰的自组装肽用作功能性超分子生物材料的构建块引起了广泛关注。最近，有人提出动态肽库（DPL）可在非特异性蛋白酶存在的情况下，从二肽输入的动态交换混合物中选择自组装材料，其中肽序列根据其自组装倾向进行选择和扩增。结果表明，混合序列的DPL（例如从双亮氨酸L和双苯丙氨酸F的混合物开始）的结果与单独的L和F库（分别产生F和L的自组装）不同，这意味着这些序列之间的相互作用可能会破坏自组装。在本研究中，使用粗粒度分子动力学（CG-MD）模拟来理解F、L和混合库的DPL结果。CG-MD模拟表明，前体之间的相互作用会导致二肽混合物中六肽的低产率形成，并表明这种破坏能力受DPL中不同物种浓度的影响。DPL中物种之间的破坏自组装效应是动态组合化学中需要考虑的一个重要效应，因为它会影响新材料的可能发现。这项工作表明，计算筛选和实验筛选可以互补结合使用，为发现新的超分子肽纳米结构提供有力手段。
