Subramanian Nandhitha, Schumann-Gillett Alexandra, Mark Alan E, O'Mara Megan L
School of Chemistry and Molecular Biosciences (SCMB), University of Queensland, Brisbane, QLD 4072, Australia; Research School of Chemistry (RSC), The Australian National University, Canberra, ACT 2601, Australia.
School of Chemistry and Molecular Biosciences (SCMB), University of Queensland, Brisbane, QLD 4072, Australia.
Biochim Biophys Acta. 2016 Apr;1858(4):776-82. doi: 10.1016/j.bbamem.2015.12.025. Epub 2015 Dec 23.
The apparent activity of the multidrug transporter P-glycoprotein (P-gp) is enhanced by the presence of cholesterol. Whether this is due to the direct effect of cholesterol on the activity of P-gp, its effect on the local concentration of substrate in the membrane, or its effect on the rate of entry of the drug into the cell, is unknown. In this study, molecular dynamics simulation techniques coupled with potential of mean force calculations have been used to investigate the role of cholesterol in the movement of four P-gp substrates across a POPC bilayer in the presence or absence of 10% cholesterol. The simulations suggest that the presence of cholesterol lowers the free energy associated with entering the middle of the bilayer in a substrate-specific manner. These findings suggest that P-gp substrates may preferentially accumulate in cholesterol-rich regions of the membrane, which may explain its enhanced transport activity.
多药转运蛋白P-糖蛋白（P-gp）的表观活性会因胆固醇的存在而增强。这是由于胆固醇对P-gp活性的直接作用、其对膜中底物局部浓度的影响，还是其对药物进入细胞速率的影响，目前尚不清楚。在本研究中，分子动力学模拟技术与平均力势计算相结合，用于研究在存在或不存在10%胆固醇的情况下，胆固醇在四种P-gp底物跨POPC双层膜移动中的作用。模拟结果表明，胆固醇的存在以底物特异性方式降低了与进入双层膜中间相关的自由能。这些发现表明，P-gp底物可能优先在膜中富含胆固醇的区域积累，这可能解释了其增强的转运活性。
