Nierzwicki L, Wieczor M, Censi V, Baginski M, Calucci L, Samaritani S, Czub J, Forte C
Department of Physical Chemistry, Gdansk University of Technology, ul. Narutowicza 11/12, 80-233 Gdansk, Poland.
Phys Chem Chem Phys. 2015 Jan 14;17(2):1458-68. doi: 10.1039/c4cp04360j. Epub 2014 Nov 28.
In this study, the interaction of cisplatin (1) and two potential antitumoral Pt(II) complexes (2 and 3) with a model DMPC bilayer was investigated by multinuclear NMR spectroscopy and MD simulations in order to understand its implication for the different antitumoral properties shown by the three complexes. In particular, (31)P, (13)C and (2)H solid state NMR experiments were performed to obtain information on the phase structure, phase transitions and structural and dynamic changes in the phospholipid bilayer upon interaction with the platinum complexes. On the other hand, MD calculations yielded free energy profiles for the different complexes across the bilayer; the results were analysed to obtain MD predictions on complex distribution with respect to the bilayer, as well as to establish their effects on the conformational equilibrium of the DMPC acyl chains. The combination of NMR and MD approaches highlighted that, whereas the more hydrophilic cisplatin tends to remain in the polar head group region causing a decrease in flexibility of the bilayer, the two new complexes enter into the bilayer. In particular, complex 2 is preferentially located relatively close to the surface, only slightly affecting the bilayer structure and mobility, while complex 3 penetrates more deeply, strongly perturbing the bilayer and giving rise to lateral phase separation.
在本研究中，通过多核核磁共振光谱和分子动力学模拟研究了顺铂（1）以及两种潜在的抗肿瘤铂（II）配合物（2和3）与模型二肉豆蔻酰磷脂酰胆碱（DMPC）双层的相互作用，以了解其对三种配合物所表现出的不同抗肿瘤特性的影响。具体而言，进行了磷-31、碳-13和氢-2固态核磁共振实验，以获取磷脂双层与铂配合物相互作用时的相结构、相变以及结构和动力学变化的信息。另一方面，分子动力学计算得出了不同配合物穿过双层的自由能分布；对结果进行分析，以获得关于配合物在双层中的分布的分子动力学预测，以及确定它们对DMPC酰基链构象平衡的影响。核磁共振和分子动力学方法的结合突出表明，亲水性更强的顺铂倾向于留在极性头部基团区域，导致双层的柔韧性降低，而两种新配合物则进入双层。特别是，配合物2优先位于相对靠近表面的位置，仅对双层结构和流动性有轻微影响，而配合物3则更深地渗透，强烈扰动双层并导致横向相分离。
