de Sá Matheus Malta, Sresht Vishnu, Rangel-Yagui Carlota Oliveira, Blankschtein Daniel
†Department of Chemical Engineering, Massachusetts Institute of Technology, Cambridge, Massachusetts 02139-4307, United States.
‡School of Pharmaceutical Sciences, Department of Pharmacy, University of São Paulo, São Paulo, SP Brazil.
Langmuir. 2015 Apr 21;31(15):4503-12. doi: 10.1021/acs.langmuir.5b00178. Epub 2015 Apr 7.
Coarse-grained molecular dynamics simulations are used to calculate the free energies of transfer of miltefosine, an alkylphosphocholine anticancer agent, from water to lipid bilayers to study its mechanism of interaction with biological membranes. We consider bilayers containing lipids with different degrees of unsaturation: dipalmitoylphosphatidylcholine (DPPC, saturated, containing 0%, 10%, and 30% cholesterol), dioleoylphosphatidylcholine (DOPC, diunsaturated), palmitoyloleoylphosphatidylcholine (POPC, monounsaturated), diarachidonoylphosphatidylcholine (DAPC, polyunsaturated), and dilinoleylphosphatidylcholine (DUPC, polyunsaturated). These free energies, calculated using umbrella sampling, were used to compute the partition coefficients (K) of miltefosine between water and the lipid bilayers. The K values for the bilayers relative to that of pure DPPC were found to be 5.3 (DOPC), 7.0 (POPC), 1.0 (DAPC), 2.2 (DUPC), 14.9 (10% cholesterol), and 76.2 (30% cholesterol). Additionally, we calculated the free energy of formation of miltefosine-cholesterol complexes by pulling the surfactant laterally in the DPPC + 30% cholesterol system. The free energy profile that we obtained provides further evidence that miltefosine tends to associate with cholesterol and has a propensity to partition into lipid rafts. We also quantified the kinetics of the transport of miltefosine through the various bilayers by computing permeance values. The highest permeance was observed in DUPC bilayers (2.28 × 10(-2) m/s) and the lowest permeance in the DPPC bilayer with 30% cholesterol (1.10 × 10(-7) m/s). Our simulation results show that miltefosine does indeed interact with lipid rafts, has a higher permeability in polyunsaturated, loosely organized bilayers, and has higher flip-flop rates in specific regions of cellular membranes.
粗粒度分子动力学模拟用于计算米托蒽醌（一种烷基磷胆碱抗癌剂）从水相转移至脂质双层的自由能，以研究其与生物膜的相互作用机制。我们考虑了含有不同不饱和度脂质的双层膜：二棕榈酰磷脂酰胆碱（DPPC，饱和，含0%、10%和30%胆固醇）、二油酰磷脂酰胆碱（DOPC，二不饱和）、棕榈酰油酰磷脂酰胆碱（POPC，单不饱和）、二花生四烯酰磷脂酰胆碱（DAPC，多不饱和）和二亚油酰磷脂酰胆碱（DUPC，多不饱和）。使用伞形抽样计算得到的这些自由能，用于计算米托蒽醌在水相和脂质双层之间的分配系数（K）。相对于纯DPPC双层膜，其他双层膜的K值分别为5.3（DOPC）、7.0（POPC）、1.0（DAPC）、2.2（DUPC）、14.9（10%胆固醇）和76.2（30%胆固醇）。此外，我们通过在DPPC + 30%胆固醇体系中横向拉动表面活性剂，计算了米托蒽醌 - 胆固醇复合物的形成自由能。我们获得的自由能曲线进一步证明米托蒽醌倾向于与胆固醇结合，并具有分配到脂筏中的倾向。我们还通过计算渗透值来量化米托蒽醌通过各种双层膜的运输动力学。在DUPC双层膜中观察到最高的渗透率（2.28×10⁻² m/s），在含30%胆固醇的DPPC双层膜中渗透率最低（1.10×10⁻⁷ m/s）。我们的模拟结果表明，米托蒽醌确实与脂筏相互作用，在多不饱和、结构松散的双层膜中具有更高的渗透性，并且在细胞膜的特定区域具有更高的翻转速率。
