Instituto de Tecnologia Química e Biológica, Universidade Nova de Lisboa, Av. da República, EAN, 2780-157 Oeiras, Portugal.
J Am Chem Soc. 2011 Apr 6;133(13):5042-52. doi: 10.1021/ja111001v. Epub 2011 Mar 15.
We present here the first comprehensive structural characterization of peptide dendrimers using molecular simulation methods. Multiple long molecular dynamics simulations are used to extensively sample the conformational preferences of five third-generation peptide dendrimers, including some known to bind aquacobalamine. We start by analyzing the compactness of the conformations thus sampled using their radius of gyration profiles. A more detailed analysis is then performed using dissimilarity measures, principal coordinate analysis, and free energy landscapes, with the aim of identifying groups of similar conformations. The results point to a high conformational flexibility of these molecules, with no clear "folded state", although two markedly distinct behaviors were found: one of the dendrimers displayed mostly compact conformations clustered into distinct basins (rough landscape), while the remaining dendrimers displayed mainly noncompact conformations with no significant clustering (downhill landscape). This study brings new insight into the conformational behavior of peptide dendrimers and may provide better routes for their functional design. In particular, we propose a yet unsynthesized peptide dendrimer that might exhibit enhanced ability to coordinate aquocobalamin.
我们在这里使用分子模拟方法首次全面表征了肽树状大分子的结构。使用多个长分子动力学模拟来广泛采样五种第三代肽树状大分子的构象偏好，包括已知结合水钴胺素的一些。我们首先使用它们的回转半径分布来分析采样构象的紧凑性。然后使用不相似性度量、主坐标分析和自由能景观进行更详细的分析，目的是识别相似构象的组。结果表明这些分子具有很高的构象灵活性，没有明确的“折叠状态”，尽管发现了两种截然不同的行为：一种树状大分子显示出大多是紧凑的构象，聚集在不同的盆地中（粗糙景观），而其余的树状大分子显示出主要是非紧凑的构象，没有明显的聚集（下坡景观）。这项研究为肽树状大分子的构象行为提供了新的见解，并可能为它们的功能设计提供更好的途径。特别是，我们提出了一种尚未合成的肽树状大分子，它可能具有增强的结合水钴胺素的能力。
