State Key Laboratory of Chemical Oncogenomics, School of Chemical Biology and Biotechnology , Peking University Shenzhen Graduate School , Shenzhen 518055 , China.
ACS Nano. 2019 Apr 23;13(4):4455-4468. doi: 10.1021/acsnano.8b09741. Epub 2019 Mar 19.
The molecular design of peptide-assembled nanostructures relies on extensive knowledge pertaining to the relationship between conformational features of peptide constituents and their behavior regarding self-assembly, and characterizing the conformational details of peptides during their self-assembly is experimentally challenging. Here, we demonstrate that a hybrid-resolution modeling method can be employed to investigate the role that conformation plays during the assembly of terminally capped diphenylalanines (FF) through microsecond simulations of hundreds or thousands of peptides. Our simulations discovered tubular or vesicular nanostructures that were consistent with experimental observation while reproducing critical self-assembly concentration and secondary structure contents in the assemblies that were measured in our experiments. The atomic details provided by our method allowed us to uncover diverse FF conformations and conformation dependence of assembled nanostructures. We found that the assembled morphologies and the molecular packing of FFs in the observed assemblies are linked closely with side-chain angle and peptide bond orientation, respectively. Of various conformations accessible to soluble FFs, only a select few are compatible with the assembled morphologies in water. A conformation resembling a FF crystal, in particular, became predominant due to its ability to permit highly ordered and energetically favorable FF packing in aqueous assemblies. Strikingly, several conformations incompatible with the assemblies arose transiently as intermediates, facilitating key steps of the assembly process. The molecular rationale behind the role of these intermediate conformations were further explained. Collectively, the structural details reported here advance the understanding of the FF self-assembly mechanism, and our method shows promise for studying peptide-assembled nanostructures and their rational design.
肽组装纳米结构的分子设计依赖于对肽组成部分构象特征与其自组装行为之间关系的广泛了解，并且在肽自组装过程中对肽构象细节进行表征在实验上具有挑战性。在这里，我们证明了一种混合分辨率建模方法可用于通过对数百或数千个肽进行微秒模拟来研究末端封端二苯丙氨酸（FF）在组装过程中构象所起的作用。我们的模拟发现了管状或囊泡状纳米结构，这些结构与实验观察结果一致，同时复制了我们实验中测量的组装体中的关键自组装浓度和二级结构含量。我们方法提供的原子细节使我们能够揭示 FF 的多种构象和组装纳米结构的构象依赖性。我们发现，组装形态和观察到的组装体中 FF 的分子堆积与侧链角度和肽键取向分别密切相关。在可溶性 FF 可获得的各种构象中，只有少数几种与水中的组装形态兼容。特别是类似于 FF 晶体的构象由于其能够允许在水溶液组装体中形成高度有序且能量有利的 FF 堆积，因此变得占主导地位。引人注目的是，作为中间体出现了几种与组装体不兼容的构象，促进了组装过程的关键步骤。这些中间构象的作用的分子原理进一步得到了解释。总的来说，这里报道的结构细节推进了对 FF 自组装机制的理解，并且我们的方法显示了研究肽组装纳米结构及其合理设计的潜力。
