Bioinformatik, Institut für Biochemie, Emil-Fischer-Centrum, Friedrich-Alexander-Universität Erlangen-Nürnberg, (FAU), Fahrstraße 17, 91054, Erlangen, Germany.
Sci Rep. 2018 Mar 29;8(1):5374. doi: 10.1038/s41598-018-23624-8.
Synthetic analogues of mycobacterial trehalose-dimycolate such as trehalose acyl esters have been proposed as novel adjuvants for vaccination. They induce an immune response by binding to the macrophage C-type lectin receptor Mincle. The binding site of trehalose is known, but there is yet only very limited structural information about the binding mode of the acyl esters. Here, we performed a systematic molecular dynamics study of trehalose mono-and diesters with different chain lengths. All acyl chains investigated exhibited a high flexibility and interacted almost exclusively with a hydrophobic groove on Mincle. Despite the limited length of this hydrophobic groove, the distal parts of the longer monoesters can still form additional interactions with this surface region due to their conformational flexibility. In diesters, a certain length of the second acyl chain is required to contact the hydrophobic groove. However, a stable concomitant accommodation of both acyl chains in the groove is hampered by the conformational rigidity of Mincle. Instead, multiple dynamic interaction modes are observed, in which the second acyl chain contributes to binding. This detailed structural information is considered helpful for the future design of more affine ligands that may foster the development of novel adjuvants.
分枝杆菌海藻糖二分枝酸的合成类似物，如海藻糖酰酯，被提议作为新型疫苗佐剂。它们通过与巨噬细胞 C 型凝集素受体 Mincle 结合来诱导免疫反应。海藻糖的结合位点是已知的，但关于酰酯的结合模式的结构信息仍然非常有限。在这里，我们对具有不同链长的海藻糖单酯和二酯进行了系统的分子动力学研究。所有研究的酰基链都表现出高度的灵活性，并且几乎仅与 Mincle 上的疏水性凹槽相互作用。尽管该疏水性凹槽的长度有限，但较长的单酯的远端部分仍由于其构象灵活性而可以与该表面区域形成额外的相互作用。在二酯中，第二个酰基链需要一定的长度才能与疏水性凹槽接触。然而，由于 Mincle 的构象刚性，两个酰基链在凹槽中的稳定同时容纳受到阻碍。相反，观察到多种动态相互作用模式，其中第二个酰基链有助于结合。这些详细的结构信息被认为有助于设计更亲和的配体，从而促进新型佐剂的开发。
