Center for Condensed Matter Theory, Department of Physics , Indian Institute of Science , Bangalore 560012 , India.
Department of Chemical Engineering, Center for Biosystems Science and Engineering , Indian Institute of Science , Bangalore 560012 , India.
J Chem Theory Comput. 2018 Jul 10;14(7):3825-3839. doi: 10.1021/acs.jctc.8b00119. Epub 2018 Jun 13.
The understanding of dendrimer interactions with cell membranes has great importance in drug/gene delivery based therapeutics. Although molecular simulations have been used to understand the nature of dendrimer interactions with lipid membranes, its dependency on available force field parameters is poorly understood. In this study, we have carried out fully atomistic molecular dynamics (MD) simulations of a protonated G3 poly(amido amine) (PAMAM) dendrimer-dimyristoylphosphatidylcholine (DMPC) lipid bilayer complex using three different force fields (FFs) namely, CHARMM, GAFF, and GROMOS in the presence of explicit water to understand the structure of the lipid-dendrimer complex and nature of their interaction. CHARMM and GAFF dendrimers initially in contact with the lipid head groups were found to move away from the lipid bilayer during the course of simulation; however, the dendrimer remained strongly bound to the lipid head groups with the GROMOS FF. Potential of the mean force (PMF) computations of the dendrimer along the bilayer normal showed a repulsive barrier (∼20 kcal/mol) between dendrimer and lipid bilayer in the case of CHARMM and GAFF force fields. In contrast, an attractive interaction (∼40 kcal/mol) is obtained with the GROMOS force field, consistent with experimental observations of membrane binding observed with lower generation G3 PAMAM dendrimers. This difference with the GROMOS dendrimer is attributed to the strong dendrimer-lipid interaction and lowered surface hydration of the dendrimer. Assessing the role of solvent, we find that the CHARMM and GAFF dendrimers strongly bind to the lipid bilayer with an implicit solvent (Generalized Born) model, whereas binding is not observed with explicit water (TIP3P). The opposing nature of dendrimer-membrane interactions in the presence of explicit and implicit solvents demonstrates that hydration effects play an important role in modulating the dendrimer-lipid interaction warranting a case for refinement of the existing dendrimer/lipid force fields.
树突状聚合物与细胞膜的相互作用的理解在基于药物/基因传递的治疗中具有重要意义。尽管分子模拟已被用于理解树突状聚合物与脂质膜的相互作用的性质，但对其对可用力场参数的依赖性的理解还很有限。在这项研究中，我们使用三种不同的力场（CHARMM、GAFF 和 GROMOS），在存在显式水的情况下，对质子化的 G3 聚（酰胺胺）（PAMAM）树突状聚合物-二肉豆蔻酰磷脂酰胆碱（DMPC）脂质双层复合物进行了全原子分子动力学（MD）模拟，以了解脂质-树突状聚合物复合物的结构及其相互作用的性质。CHARMM 和 GAFF 树突状聚合物最初与脂质头部基团接触，在模拟过程中被发现远离脂质双层；然而，GROMOS 力场下的树突状聚合物仍然与脂质头部基团强烈结合。树突状聚合物沿双层法向的平均势能（PMF）计算显示，在 CHARMM 和 GAFF 力场的情况下，树突状聚合物与脂质双层之间存在排斥势垒（约 20 kcal/mol）。相比之下，与 GROMOS 力场得到的是吸引力相互作用（约 40 kcal/mol），这与低代 G3 PAMAM 树突状聚合物观察到的膜结合实验观察结果一致。与 GROMOS 树突状聚合物的这种差异归因于强的树突状聚合物-脂质相互作用和降低的树突状聚合物表面水合作用。评估溶剂的作用，我们发现 CHARMM 和 GAFF 树突状聚合物与含有隐式溶剂（广义 Born）模型的脂质双层强烈结合，而在含有显式水（TIP3P）的情况下则没有观察到结合。在显式和隐式溶剂存在下树突状聚合物-膜相互作用的相反性质表明，水合作用在调节树突状聚合物-脂质相互作用中起着重要作用，这证明有必要对现有的树突状聚合物/脂质力场进行改进。
