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.

中文翻译：

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树枝状大分子与脂质双层的相互作用：力场的比较和隐式和显式溶剂化的影响。

树枝状聚合物与细胞膜相互作用的理解在基于药物/基因递送的治疗剂中非常重要。尽管已经使用分子模拟来理解树枝状大分子与脂质膜相互作用的性质，但是人们对它对可用力场参数的依赖性知之甚少。在这项研究中，我们使用三个不同的力场（FFs），即CHARMM，GAFF，对质子化的G3聚氨基酰胺（PAMAM）树状聚合物-二肉豆蔻酰磷脂酰胆碱（DMPC）脂质双层复合物进行了完全原子分子动力学（MD）模拟。 ，和GROMOS在明显的水存在下了解脂质-树状聚合物复合物的结构及其相互作用的性质。发现在模拟过程中，最初与脂质头基团接触的CHARMM和GAFF树状大分子从脂质双层移开。但是，树状大分子仍然与GROMOS FF牢固地结合在脂质头基上。在CHARMM和GAFF力场的情况下，沿双分子法线计算的树枝状聚合物的平均力（PMF）的潜力显示出树枝状聚合物和脂质双层之间的排斥屏障（〜20 kcal / mol）。相反，利用GROMOS力场获得了有吸引力的相互作用（约40 kcal / mol），这与用较低代G3 PAMAM树状聚合物观察到的膜结合的实验观察结果一致。与GROMOS树枝状聚合物的这种差异归因于树枝状聚合物与脂质的强相互作用和树枝状聚合物表面水合降低。评估溶剂的作用，我们发现，CHARMM和GAFF树状大分子与隐性溶剂（广义Born）模型与脂质双层牢固结合，而对显性水（TIP3P）则未观察到结合。在显性和隐性溶剂存在下，树枝状聚合物-膜相互作用的相反性质表明，水合效应在调节树枝状聚合物-脂质相互作用中起着重要作用，因此有必要完善现有的树枝状聚合物/脂质力场。