Molecular Pharmacology and Toxicology, Department of Medical Biology, Faculty of Health Sciences, UiT-The Arctic University of Norway, NO-9037Tromsø, Norway.
Department of Pharmacy and Biotechnology, Alma Mater Studiorum-Università di Bologna, Via Belmeloro 6, I-40126 Bologna, Italy.
J Chem Inf Model. 2020 Apr 27;60(4):2294-2303. doi: 10.1021/acs.jcim.0c00163. Epub 2020 Apr 15.
γ-Aminobutyric acid (GABA) is the main inhibitory neurotransmitter in the central nervous system (CNS). Dysfunctional GABAergic neurotransmission is associated with numerous neurological and neuropsychiatric disorders. The GABA receptor (GABA-R) is a heterodimeric class C G protein-coupled receptor (GPCR) comprised of GABA and GABA subunits. The orthosteric binding site for GABA is located in the extracellular (VFT) domain of the GABA. Knowledge about molecular mechanisms and druggable receptor conformations associated with activation is highly important to understand the receptor function and for rational drug design. Currently, the conformational changes of the receptor upon activation are not well described. On the basis of other class C members, the VFT is proposed to fluctuate between an open/inactive and closed/active state and one of these conformations is stabilized upon ligand binding. In the present study, we investigated the dynamics of the GABA-R VFT in the apo form by combining unbiased molecular dynamics with path-metadynamics. Our simulations confirmed the open/inactive and closed/active state as the main conformations adopted by the receptor. Sizeable energy barriers were found between stable minima, suggesting a relatively slow interconversion. Previously undisclosed metastable states were also identified, which might hold potential for future drug discovery efforts.
γ-氨基丁酸（GABA）是中枢神经系统（CNS）中的主要抑制性神经递质。GABA 能神经传递功能障碍与许多神经和神经精神疾病有关。GABA 受体（GABA-R）是由 GABA 和 GABA 亚基组成的异源二聚体 C 类 G 蛋白偶联受体（GPCR）。GABA 的正位结合位点位于 GABA 的细胞外（VFT）结构域。了解与激活相关的分子机制和可成药的受体构象对于理解受体功能和合理药物设计非常重要。目前，关于受体激活时的构象变化还没有很好的描述。基于其他 C 类成员，VFT 被提议在开放/无活性和关闭/活性状态之间波动，并且其中一种构象在配体结合时稳定下来。在本研究中，我们通过结合无偏分子动力学和路径元动力学研究了apo 形式下 GABA-R VFT 的动力学。我们的模拟证实了开放/无活性和关闭/活性状态是受体采用的主要构象。在稳定的最小值之间发现了相当大的能量障碍，这表明相互转化相对较慢。还确定了以前未公开的亚稳态，这可能为未来的药物发现工作提供了潜力。
