Institut für Physikalische Chemie, Universität Freiburg, Albertstraße 21, 79104 Freiburg, Germany.
Institut für Physikalische und Theoretische Chemie, Technische Universität Braunschweig, Gaußstraße 17, 38106 Braunschweig, Germany.
Phys Chem Chem Phys. 2022 Jun 15;24(23):14219-14227. doi: 10.1039/d2cp01140a.
We study the diffusion of cocaine through a DMPC lipid bilayer as an example of a protonable, amphiphilic molecule passing a biological membrane. Using classical molecular dynamics simulations, the free energy surfaces are computed applying the umbrella sampling technique for the protonated and the neutral molecule. For the combined surface, we numerically solve the diffusion equation at constant flow and for time-dependent concentrations. We find a potential of mean force dominated by a barrier of 3.5 kcal mol within the membrane, and a pH-dependent entry and exit barrier of 2.0 kcal mol and 4.1 kcal mol, respectively. This behaviour can be rationalized chemically by the amphiphilic nature of the molecule and the change of its protonation state while passing the membrane. Diffusion through the barriers is 3.5 times slower than along the membrane, and the typical time scale of passage amounts to 0.1 ms. We discuss biochemical and medical implications of our findings, and comment on the mechanism of the drug passing the blood-brain barrier.
我们以质子化两亲性分子通过生物膜为例，研究了可卡因在 DMPC 脂质双层中的扩散。通过经典分子动力学模拟，我们应用伞状采样技术计算了质子化和中性分子的自由能表面。对于组合表面，我们在恒定流和随时间变化的浓度下数值求解扩散方程。我们发现，在膜内，平均势由 3.5 kcal/mol 的势垒主导，而 pH 值依赖性的进入和退出势垒分别为 2.0 kcal/mol 和 4.1 kcal/mol。这种行为可以通过分子的两亲性和其在穿过膜时质子化状态的变化来进行化学解释。通过屏障的扩散速度比沿膜的扩散速度慢 3.5 倍，典型的通过时间尺度约为 0.1 ms。我们讨论了我们发现的生化和医学意义，并评论了药物通过血脑屏障的机制。
