Department of Chemistry, Osaka Prefecture University, 1-1, Gakuen-cho, Sakai, Osaka, 599-8531, Japan.
RIMED, Osaka Prefecture University, 1-1, Gakuen-cho, Sakai, Osaka, 599-8531, Japan.
Phys Chem Chem Phys. 2022 Nov 2;24(42):26070-26082. doi: 10.1039/d2cp03678a.
Biomembrane permeation represents a major barrier to pharmacokinetics. During preclinical drug discovery, the coefficients of the permeation of molecules through lipid bilayers account for a valuable property of such molecules. Therefore, the control of the permeation of molecules through lipid bilayers is an essential factor in drug design, and the estimation of the permeation phenomena is a crucial study in pharmacy. Thus, there are many published studies on the theoretical estimations of permeation coefficients. Here, we propose a molecular dynamics (MD) simulation method for estimating the permeation of small molecules through lipid bilayers based on the free-energy reaction network (FERN) analysis. In this method, the collective variables (CVs) of the free energy calculations explicitly include the conformational changes in the rotational bonds of the solute molecules. The advantages of the present method over the other method are that it is possible to estimate reaction pathways and their reaction rates, , permeation coefficients or passage times, in multidimensional space spanned by CVs though conventional methods such as the umbrella sampling method and target MDs often dealt with a few degrees of freedom. To demonstrate the efficacy of our method, we calculate the coefficients of the permeation of three small aromatic peptides, namely -acetylphenylalanineamide (Ac-Phe-NH2 or NAFA), -acetyltyrosineamide (Ac-Tyr-NH2 or NAYA), and -acetyltryptophanamide (Ac-Trp-NH2 or NATA), through a 1,2-dioleoyl--glycero-3-phosphocholine (DOPC) lipid bilayer. In these cases we adopted one CV for the permeation direction and four CVs for the internal rotational coordinates. The results reveal that the permeation coefficients of NAFA, NAYA, and NATA are 1.7 × 10, 0.51 × 10, and 5.7 × 10 cm s, respectively. Compared with the experimental data, our simulation results followed the same trend, , NAFA > NATA > NAYA. By analyzing the structures of metastable points of the solute molecules, our simulation result reveals that the aforementioned trend is caused by the differences in stability among their rotamers. Furthermore, we evaluate the statistical fluctuation of the rotamers, and the time scale of flipping the side chain reveals that the structures rigidify as the ligand moves deeper into the membrane.
生物膜渗透是药代动力学的主要障碍。在临床前药物发现过程中，分子通过脂质双层的渗透系数是此类分子的重要特性。因此，控制分子通过脂质双层的渗透是药物设计的一个重要因素，而渗透现象的估算则是药学中的一项关键研究。因此，有许多关于渗透系数理论估算的已发表研究。在这里，我们提出了一种基于自由能反应网络（FERN）分析的分子动力学（MD）模拟方法，用于估算小分子通过脂质双层的渗透。在该方法中，自由能计算的集体变量（CVs）明确包含溶质分子旋转键构象变化。与其他方法相比，本方法的优点在于能够在 CV 所跨越的多维空间中估算反应途径及其反应速率、渗透系数或通过时间，而传统方法，如伞状采样法和目标 MD，通常只处理少数自由度。为了证明我们方法的有效性，我们计算了三种小芳香肽（即乙酰苯丙氨酸酰胺（Ac-Phe-NH2 或 NAFA）、乙酰酪氨酸酰胺（Ac-Tyr-NH2 或 NAYA）和乙酰色氨酸酰胺（Ac-Trp-NH2 或 NATA）通过 1,2-二油酰基-sn-甘油-3-磷酸胆碱（DOPC）脂质双层的渗透系数。在这些情况下，我们采用一个 CV 用于渗透方向，四个 CV 用于内部旋转坐标。结果表明，NAFA、NAYA 和 NATA 的渗透系数分别为 1.7×10、0.51×10 和 5.7×10 cm s。与实验数据相比，我们的模拟结果遵循相同的趋势，即 NAFA>NATA>NAYA。通过分析溶质分子的亚稳态点结构，我们的模拟结果表明，上述趋势是由它们的构象异构体的稳定性差异引起的。此外，我们评估了构象异构体的统计波动，并且翻转侧链的时间尺度表明，随着配体深入膜内，结构变得更加僵硬。
