Center for Quantitative Biology, Academy for Advanced Interdisciplinary Studies, Peking University, Beijing, China; Peking-Tsinghua Center for Life Sciences, Academy for Advanced Interdisciplinary Studies, Peking University, Beijing, China; Department of Biochemistry, University of Oxford, Oxford, United Kingdom.
Department of Theoretical and Computational Biophysics, Max-Planck Institute for Biophysical Chemistry, Göttingen, Germany.
Biophys J. 2019 May 7;116(9):1658-1666. doi: 10.1016/j.bpj.2019.03.033. Epub 2019 Apr 5.
Antimicrobial peptides (AMPs) carry great potential as new antibiotics against "superbugs." Dermcidin (DCD), a broad-spectrum AMP in human sweat, has been recently crystallized in its oligomeric state and showed channel-like properties. In this work, we performed multiscale molecular dynamics simulations to study how the membrane composition influences the behavior of a transmembrane pore formed by the DCD oligomer in the hope of revealing the origin of the membrane selectivity of this AMP toward bacteria. Our results indicate that bilayers composed of various lipids (DMPC, DPPC, and DSPC) with different thicknesses result in different orientations of the DCD oligomer when embedded in lipid bilayers. The thicker the bilayer, the less tilted the channel. Cholesterol makes the bilayers more rigid and thicker, which also affects the orientation of the channel. Furthermore, we observed that the predicted conductance of the channel from computational electrophysiology simulations is related to its orientation in the lipid bilayer: the larger the tilt, the larger the conductance. Our results indicate that the membrane composition has a significant influence on the activity of the DCD channel, with thicker, cholesterol-rich membranes showing lower conductance than that of thinner membranes.
抗菌肽 (AMPs) 作为对抗“超级细菌”的新型抗生素具有巨大潜力。人汗中的广谱 AMP 皮促素 (DCD) 最近已被结晶为其寡聚状态，并显示出通道样特性。在这项工作中，我们进行了多尺度分子动力学模拟，以研究膜组成如何影响由 DCD 寡聚体形成的跨膜孔的行为，希望揭示这种 AMP 对细菌的膜选择性的起源。我们的结果表明，由不同厚度的各种脂质 (DMPC、DPPC 和 DSPC) 组成的双层导致 DCD 寡聚体在嵌入脂质双层时具有不同的取向。双层越厚，通道的倾斜度越小。胆固醇使双层更加刚性和厚实，这也会影响通道的取向。此外，我们观察到计算电生理学模拟预测的通道电导与其在脂质双层中的取向有关：倾斜度越大，电导越大。我们的结果表明，膜组成对 DCD 通道的活性有显著影响，较厚、富含胆固醇的膜的电导低于较薄的膜。
