Department of Physics, Technical University of Catalonia-Barcelona Tech, 08034 Barcelona, Spain.
School of Pharmacy, Shanghai Jiaotong University, Shanghai 200240, China.
Int J Mol Sci. 2021 Mar 11;22(6):2842. doi: 10.3390/ijms22062842.
The interactions at the atomic level between small molecules and the main components of cellular plasma membranes are crucial for elucidating the mechanisms allowing for the entrance of such small species inside the cell. We have performed molecular dynamics and metadynamics simulations of tryptophan, serotonin, and melatonin at the interface of zwitterionic phospholipid bilayers. In this work, we will review recent computer simulation developments and report microscopic properties, such as the area per lipid and thickness of the membranes, atomic radial distribution functions, angular orientations, and free energy landscapes of small molecule binding to the membrane. Cholesterol affects the behaviour of the small molecules, which are mainly buried in the interfacial regions. We have observed a competition between the binding of small molecules to phospholipids and cholesterol through lipidic hydrogen-bonds. Free energy barriers that are associated to translational and orientational changes of melatonin have been found to be between 10-20 kJ/mol for distances of 1 nm between melatonin and the center of the membrane. Corresponding barriers for tryptophan and serotonin that are obtained from reversible work methods are of the order of 10 kJ/mol and reveal strong hydrogen bonding between such species and specific phospholipid sites. The diffusion of tryptophan and melatonin is of the order of 10-7 cm2/s for the cholesterol-free and cholesterol-rich setups.
在阐明允许这些小分子进入细胞的机制方面，小分子与细胞浆膜主要成分在原子水平上的相互作用至关重要。我们在两性离子磷脂双层膜的界面处对色氨酸、血清素和褪黑素进行了分子动力学和元动力学模拟。在这项工作中，我们将回顾最近的计算机模拟进展，并报告微观性质，如每个脂质的面积和膜的厚度、原子径向分布函数、角取向以及小分子与膜结合的自由能景观。胆固醇会影响小分子的行为，这些小分子主要埋藏在界面区域。我们观察到小分子与胆固醇通过脂质氢键结合的竞争。对于距离为 1nm 的褪黑素与膜中心之间的位置，与褪黑素的平移和取向变化相关的自由能势垒被发现约为 10-20kJ/mol。通过可逆功方法获得的色氨酸和血清素的相应势垒约为 10kJ/mol，表明这些物质与特定的磷脂位点之间存在强氢键。在无胆固醇和富含胆固醇的设置中，色氨酸和褪黑素的扩散约为 10-7cm2/s。
