The CXC chemokine receptor 1 (CXCR1) is an important member of the G protein-coupled receptor (GPCR) family in which the extracellular N-terminal domain has been implicated in ligand binding and selectivity. The structure of this domain has not yet been elucidated due to its inherent dynamics, but experimental evidence points toward membrane-dependent organization and dynamics. To gain molecular insight into the interaction of the N-terminal domain with the membrane bilayer, we performed a series of microsecond time scale atomistic simulations of the N-terminal domain of CXCR1 in the presence and absence of POPC bilayers. Our results show that the peptide displays a high propensity to adopt a β-sheet conformation in the presence of the membrane bilayer. The interaction of the peptide with the membrane bilayer was found to be transient in our simulations. Interestingly, a scrambled peptide, containing the same residues in a randomly varying sequence, did not exhibit membrane-modulated structural dynamics. These results suggest that sequence-dependent electrostatics, modulated by the membrane, could play an important role in folding of the N-terminal domain. We believe that our results reinforce the emerging paradigm that cellular membranes could be important modulators of function of G protein-coupled receptors such as CXCR1.

CXC趋化因子受体1（CXCR1）是G蛋白偶联受体（GPCR）家族的重要成员，在该家族中，胞外N端结构域与配体结合和选择性有关。由于其固有的动力学，尚未阐明该结构域的结构，但实验证据表明膜依赖的组织和动力学。为了获得分子对N末端域与膜双层相互作用的分子认识，我们在存在和不存在POPC双层的情况下，对CXCR1的N末端域进行了一系列微秒级的原子模拟。我们的结果表明，在存在膜双层的情况下，该肽表现出很高的采用β-折叠构象的倾向。在我们的模拟中，发现肽与膜双层的相互作用是瞬时的。有趣的是，在随机变化的序列中包含相同残基的加扰肽没有表现出膜调节的结构动力学。这些结果表明，由膜调节的依赖序列的静电可能在N末端结构域的折叠中起重要作用。我们相信我们的结果加强了新兴的范式，即细胞膜可能是G蛋白偶联受体（例如CXCR1）功能的重要调节剂。在N末端结构域的折叠中可以起重要作用。我们相信我们的结果加强了新兴的范式，即细胞膜可能是G蛋白偶联受体（如CXCR1）功能的重要调节剂。在N末端结构域的折叠中可能起重要作用。我们相信我们的结果加强了新兴的范式，即细胞膜可能是G蛋白偶联受体（如CXCR1）功能的重要调节剂。