Frimann Tine Maja, Ko Suk Kyu, Harris Pernille, Bukrinski Jens Thostrup, Peters Günther H J
Department of Chemistry, Technical University of Denmark, Lyngby, Denmark.
Department of Chemistry, H.C. Ørsted Institute, University of Copenhagen, Copenhagen, Denmark.
J Biomol Struct Dyn. 2023 Jul;41(11):5007-5021. doi: 10.1080/07391102.2022.2078409. Epub 2022 May 25.
We have performed a series of multiple molecular dynamics (MD) simulations of glucagon-like peptide-1 (GLP-1) and acylated GLP-1 analogues in complex with the endogenous receptor (GLP-1R) to obtain a molecular understanding of how fatty acid (FA) chain structure, acylation position on the peptide, and presence of a linker affect the binding. MD simulations were analysed to extract heatmaps of receptor-peptide interaction patterns and to determine the free energy of binding using the molecular mechanics Poisson-Boltzmann surface area (MM-PBSA) approach. The extracted free energies from MM-PBSA calculations are in qualitative agreement with experimentally determined potencies. Furthermore, the interaction patterns seen in the receptor-GLP-1 complex simulations resemble previously reported binding interactions validating the simulations. Analysing the receptor-GLP-1 analogue complex simulations, we found that the major differences between the systems stem from FA interactions and positioning of acylation in the peptide. Hydrophobic interactions between the FA chain and a hydrophobic patch on the extracellular domain contribute significantly to the binding affinity. Acylation on Lys26 resulted in noticeably more interactions between the FA chain and the extracellular domain hydrophobic patch than found for acylation on Lys34 and Lys38, respectively. The presence of a charged linker between the peptide and FA chain can potentially stabilise the complex by forming hydrogen bonds to arginine residues in the linker region between the extracellular domain and the transmembrane domain. A molecular understanding of the fatty acid structure and its effect on binding provides important insights into designing acylated agonists for GLP-1R.Communicated by Ramaswamy H. Sarma.
我们对胰高血糖素样肽-1（GLP-1）和酰化GLP-1类似物与内源性受体（GLP-1R）形成的复合物进行了一系列多分子动力学（MD）模拟，以从分子层面了解脂肪酸（FA）链结构、肽上的酰化位置以及连接子的存在如何影响结合。对MD模拟进行分析，以提取受体-肽相互作用模式的热图，并使用分子力学泊松-玻尔兹曼表面积（MM-PBSA）方法确定结合自由能。从MM-PBSA计算中提取的自由能与实验测定的效价在定性上一致。此外，在受体-GLP-1复合物模拟中观察到的相互作用模式与先前报道的结合相互作用相似，从而验证了模拟结果。通过分析受体-GLP-1类似物复合物模拟，我们发现各系统之间的主要差异源于FA相互作用以及肽中酰化的位置。FA链与细胞外结构域上的疏水补丁之间的疏水相互作用对结合亲和力有显著贡献。与分别在Lys34和Lys38上的酰化相比，Lys26上的酰化导致FA链与细胞外结构域疏水补丁之间的相互作用明显更多。肽和FA链之间带电荷的连接子的存在可能通过与细胞外结构域和跨膜结构域之间的连接子区域中的精氨酸残基形成氢键来稳定复合物。对脂肪酸结构及其对结合的影响的分子理解为设计GLP-1R的酰化激动剂提供了重要见解。由Ramaswamy H. Sarma传达。
