Intermolecular Interactions in G Protein-Coupled Receptor Allosteric Sites at the Membrane Interface from Molecular Dynamics Simulations and Quantum Chemical Calculations.
Intermolecular Interactions in G Protein-Coupled Receptor Allosteric Sites at the Membrane Interface from Molecular Dynamics Simulations and Quantum Chemical Calculations.
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通过分子动力学模拟和量子化学计算，G蛋白偶联受体变构位点中的分子间相互作用。
DOI：
10.1021/acs.jcim.2c00788
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发表时间：
2022-10-10
影响因子：
5.6
通讯作者：
Tikhonova, Irina G.
中科院分区：
文献类型：
--
作者：
Ding, Tianyi;Karlov, Dmitry S.;Pino-Angeles, Almudena;Tikhonova, Irina G.
变构调节剂具有亚型选择性和更特异性的受体调节作用，被认为是G蛋白偶联受体（GPCR）药物开发中有前途的候选药物。在迄今为止已知的变构位点中，受体-脂质界面处的空腔代表了一个非特征性的结合位置，这引起了关于配体相互作用和稳定性、结合位点结构以及所有这些如何受脂质分子影响的许多问题。在这项工作中，我们分析的PAR 2，C5 aR 1，和GCGR受体在三种脂质组合物中的变构位点的相互作用，使用分子动力学模拟。此外，我们进行了量子化学计算，包括适应微扰理论（SAPT）和自然人口分析，以量化分子间相互作用的强度。我们发现，除了经典的氢键，弱极性相互作用，如O-HC，O-Br，和远程静电与骨干酰胺有助于在受体-脂质界面的变构调节剂的稳定性。在各种膜组合物中可检测到变构腔。极性原子在这种空腔中相互作用的可用性可以通过模拟的水分子来评估。虽然配体-脂质相互作用很弱，但脂质尾在配体结合的稳定性和变构腔的大小中起作用。我们讨论了在受体-脂质界面的配体结合的物理化学方面，并提出了一个化合物库丰富的弱供体基团的配体搜索在这样的网站。
Allosteric modulators are called promising candidates in G protein-coupled receptor (GPCR) drug development by displaying subtype selectivity and more specific receptor modulation. Among the allosteric sites known to date, cavities at the receptor–lipid interface represent an uncharacteristic binding location that raises many questions about the ligand interactions and stability, the binding site structure, and how all of these are affected by lipid molecules. In this work, we analyze interactions in the allosteric sites of the PAR2, C5aR1, and GCGR receptors in three lipid compositions using molecular dynamics simulations. In addition, we performed quantum chemical calculations involving the symmetry-adapted perturbation theory (SAPT) and the natural population analysis to quantify the strength of intermolecular interactions. We show that besides classical hydrogen bonds, weak polar interactions such as O–HC, O–Br, and long-range electrostatics with the backbone amides contribute to the stability of allosteric modulators at the receptor–lipid interface. The allosteric cavities are detectable in various membrane compositions. The availability of polar atoms for interactions in such cavities can be assessed by water molecules from simulations. Although ligand–lipid interactions are weak, lipid tails play a role in ligand binding pose stability and the size of allosteric cavities. We discuss physicochemical aspects of ligand binding at the receptor–lipid interface and suggest a compound library enriched by weak donor groups for ligand search in such sites.
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影响因子：
5.5
作者：
Goetz, Andreas W.;Williamson, Mark J.;Xu, Dong;Poole, Duncan;Le Grand, Scott;Walker, Ross C.
通讯作者：
Walker, Ross C.
影响因子：
64.8
作者：
Draper-Joyce CJ;Bhola R;Wang J;Bhattarai A;Nguyen ATN;Cowie-Kent I;O'Sullivan K;Chia LY;Venugopal H;Valant C;Thal DM;Wootten D;Panel N;Carlsson J;Christie MJ;White PJ;Scammells P;May LT;Sexton PM;Danev R;Miao Y;Glukhova A;Imlach WL;Christopoulos A
通讯作者：
Christopoulos A
影响因子：
18.2
作者：
Ciancetta A;Gill AK;Ding T;Karlov DS;Chalhoub G;McCormick PJ;Tikhonova IG
通讯作者：
Tikhonova IG
影响因子：
2.8
作者：
Åqvist, J;Wennerström, P;Brandsdal, BO
通讯作者：
Brandsdal, BO
影响因子：
4.3
作者：
Bruzzese, Agustin;Dalton, James A. R.;Giraldo, Jesus
通讯作者：
Giraldo, Jesus