Department of Physics, The University of Texas at San Antonio, San Antonio, TX 78249, USA.
Biochim Biophys Acta Biomembr. 2022 Sep 1;1864(9):183975. doi: 10.1016/j.bbamem.2022.183975. Epub 2022 May 30.
Glucose transporter GLUT1 is ubiquitously expressed in the human body from the red cells to the blood-brain barrier to the skeletal muscles. It is physiologically relevant to understand how GLUT1 facilitates diffusion of glucose across the cell membrane. It is also pathologically relevant because GLUT1 deficiency causes neurological disorders and anemia and because GLUT1 overexpression fuels the abnormal growth of cancer cells. This article presents a quantitative investigation of GLUT1 based on all-atom molecular-dynamics (MD) simulations of the transporter embedded in lipid bilayers of asymmetric inner-and-outer-leaflet lipid compositions, subject to asymmetric intra-and-extra-cellular environments. This is in contrast with the current literature of MD studies that have not considered both of the aforementioned asymmetries of the cell membrane. The equilibrium (unbiased) dynamics of GLUT1 shows that it can facilitate glucose diffusion across the cell membrane without undergoing large-scale conformational motions. The Gibbs free-energy profile, which is still lacking in the current literature of GLUT1, quantitatively characterizes the diffusion path of glucose from the periplasm, through an extracellular gate of GLUT1, on to the binding site, and off to the cytoplasm. This transport mechanism is validated by the experimental data that GLUT1 has low water-permeability, uptake-efflux symmetry, and 10 kcal/mol Arrhenius activation barrier around 37 °C.
葡萄糖转运蛋白 GLUT1 在人体中广泛表达,从红细胞到血脑屏障再到骨骼肌。了解 GLUT1 如何促进葡萄糖穿过细胞膜扩散在生理上是相关的。它在病理上也很重要,因为 GLUT1 缺乏会导致神经紊乱和贫血,而 GLUT1 过表达会助长癌细胞的异常生长。本文基于嵌入具有不对称内外叶层脂质组成的脂质双层中的转运蛋白的全原子分子动力学 (MD) 模拟,对 GLUT1 进行了定量研究,模拟了不对称的细胞内和细胞外环境。这与目前 MD 研究文献形成对比,后者没有考虑到细胞膜的上述两种不对称性。GLUT1 的平衡(无偏)动力学表明,它可以促进葡萄糖在细胞膜内的扩散,而无需经历大规模的构象运动。吉布斯自由能曲线,目前在 GLUT1 的文献中仍然缺乏,定量描述了葡萄糖从周质,通过 GLUT1 的细胞外门,到结合位点,再到细胞质的扩散路径。这种运输机制通过实验数据得到了验证,即 GLUT1 具有低水渗透性、摄取-外排对称性以及 37°C 左右约 10 千卡/摩尔的 Arrhenius 活化能垒。