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Accelerated molecular dynamics simulations of ligand binding to a muscarinic G-protein-coupled receptor
Quarterly Reviews of Biophysics ( IF 6.1 ) Pub Date : 2015-11-05 , DOI: 10.1017/s0033583515000153
Kalli Kappel 1 , Yinglong Miao 2 , J Andrew McCammon 1
Affiliation  

Elucidating the detailed process of ligand binding to a receptor is pharmaceutically important for identifying druggable binding sites. With the ability to provide atomistic detail, computational methods are well poised to study these processes. Here, accelerated molecular dynamics (aMD) is proposed to simulate processes of ligand binding to a G-protein-coupled receptor (GPCR), in this case the M3 muscarinic receptor, which is a target for treating many human diseases, including cancer, diabetes and obesity. Long-timescale aMD simulations were performed to observe the binding of three chemically diverse ligand molecules: antagonist tiotropium (TTP), partial agonist arecoline (ARc) and full agonist acetylcholine (ACh). In comparison with earlier microsecond-timescale conventional MD simulations, aMD greatly accelerated the binding of ACh to the receptor orthosteric ligand-binding site and the binding of TTP to an extracellular vestibule. Further aMD simulations also captured binding of ARc to the receptor orthosteric site. Additionally, all three ligands were observed to bind in the extracellular vestibule during their binding pathways, suggesting that it is a metastable binding site. This study demonstrates the applicability of aMD to protein–ligand binding, especially the drug recognition of GPCRs.

中文翻译:

配体与毒蕈碱 G 蛋白偶联受体结合的加速分子动力学模拟

阐明配体与受体结合的详细过程对于识别可药用结合位点在药学上很重要。凭借提供原子细节的能力,计算方法可以很好地研究这些过程。在这里,提出了加速分子动力学 (aMD) 来模拟配体与 G 蛋白偶联受体 (GPCR) 结合的过程,在这种情况下,M3 毒蕈碱受体是治疗许多人类疾病的靶标,包括癌症、糖尿病和肥胖。进行长时间的 aMD 模拟以观察三种化学上不同的配体分子的结合:拮抗剂噻托溴铵 (TTP)、部分激动剂槟榔碱 (ARc) 和完全激动剂乙酰胆碱 (ACh)。与早期的微秒级常规 MD 模拟相比,aMD 极大地加速了 ACh 与受体正构配体结合位点的结合以及 TTP 与细胞外前庭的结合。进一步的 aMD 模拟还捕获了 ARc 与受体正构位点的结合。此外,观察到所有三种配体在其结合途径期间都结合在细胞外前庭中,这表明它是一个亚稳态结合位点。这项研究证明了 aMD 对蛋白质-配体结合的适用性,尤其是 GPCR 的药物识别。
更新日期:2015-11-05
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