Pseudopeptides based on poly(l-lysine isophthalamide) backbone have emerged as promising drug delivery candidates due to their pH-activated membrane disruption ability. To gain molecular understanding on these novel polymeric species, we have constructed force-field parameters and simulated the behaviors of polymers with and without phenylalanine grafted as side chains under conditions compatible with different pHs. The free energy changes upon polymer permeation through membrane were calculated using the umbrella sampling technique. We show that both polymers with and without grafts interact better with the membrane under conditions compatible with lower pH. The conformational states of the polymers were investigated in water and at a water–membrane interface. On the basis of Markov state modeling results, we propose a possible advantage of the grafted polymer over the ungrafted polymer for membrane rupture because of its quicker conformational rearrangement kinetics.

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新型药物传递伪肽聚合物的脂质相互作用和构象的模拟研究

基于poly（l-赖氨酸间苯二甲酰胺骨架由于其pH激活的膜破坏能力而成为有希望的药物递送候选者。为了获得对这些新颖的聚合物种类的分子理解，我们构建了力场参数并模拟了在不同pH值兼容的条件下，有和没有苯丙氨酸作为侧链接枝的聚合物的行为。使用伞式采样技术计算了聚合物透过膜时的自由能变化。我们表明，无论有无接枝的聚合物，在与较低pH兼容的条件下均可与膜更好地相互作用。在水中和水-膜界面处研究了聚合物的构象状态。根据马尔可夫状态建模结果，