Do Hung N, Akhter Sana, Miao Yinglong
Center for Computational Biology and Department of Molecular Biosciences, University of Kansas, Lawrence, KS, United States.
Front Mol Biosci. 2021 Apr 27;8:673170. doi: 10.3389/fmolb.2021.673170. eCollection 2021.
Caffeine (CFF) is a common antagonist to the four subtypes of adenosine G-protein-coupled receptors (GPCRs), which are critical drug targets for treating heart failure, cancer, and neurological diseases. However, the pathways and mechanism of CFF binding to the target receptors remain unclear. In this study, we have performed all-atom-enhanced sampling simulations using a robust Gaussian-accelerated molecular dynamics (GaMD) method to elucidate the binding mechanism of CFF to human adenosine A receptor (AAR). Multiple 500-1,000 ns GaMD simulations captured both binding and dissociation of CFF in the AAR. The GaMD-predicted binding poses of CFF were highly consistent with the x-ray crystal conformations with a characteristic hydrogen bond formed between CFF and residue N6.55 in the receptor. In addition, a low-energy intermediate binding conformation was revealed for CFF at the receptor extracellular mouth between ECL2 and TM1. While the ligand-binding pathways of the AAR were found similar to those of other class A GPCRs identified from previous studies, the ECL2 with high sequence divergence serves as an attractive target site for designing allosteric modulators as selective drugs of the AAR.
咖啡因（CFF）是腺苷G蛋白偶联受体（GPCR）四种亚型的常见拮抗剂，而这些受体是治疗心力衰竭、癌症和神经疾病的关键药物靶点。然而，CFF与靶受体结合的途径和机制仍不清楚。在本研究中，我们使用强大的高斯加速分子动力学（GaMD）方法进行了全原子增强采样模拟，以阐明CFF与人腺苷A受体（AAR）的结合机制。多个500 - 1000纳秒的GaMD模拟捕捉到了CFF在AAR中的结合和解离。GaMD预测的CFF结合构象与X射线晶体构象高度一致，在受体中CFF与残基N6.55之间形成了特征性氢键。此外，在受体细胞外口ECL2和TM1之间发现了CFF的一种低能量中间结合构象。虽然发现AAR的配体结合途径与先前研究中鉴定的其他A类GPCR相似，但具有高序列差异的ECL2作为设计变构调节剂作为AAR选择性药物的一个有吸引力的靶点。
