Han Kyungreem, Gericke Arne, Pastor Richard W
Laboratory of Computational Biology, National Heart, Lung and Blood Institute , National Institutes of Health , Bethesda , Maryland 20892 , United States.
Department of Chemistry and Biochemistry , Worcester Polytechnic Institute , Worcester , Massachusetts 01609 , United States.
J Phys Chem B. 2020 Feb 20;124(7):1183-1196. doi: 10.1021/acs.jpcb.9b10951. Epub 2020 Feb 11.
Numerous cellular functions mediated by phosphatidylinositol (4,5)-bisphosphate (PI(4,5)P; PIP) involve clustering of the lipid as well as colocalization with other lipids. Although the cation-mediated electrostatic interaction is regarded as the primary clustering mechanism, the ion-specific nature of the intermolecular network formation makes it challenging to characterize the clusters. Here we use all-atom molecular dynamics (MD) simulations of PIP monolayers and graph-theoretic analysis to gain insight into the phenomenon. MD simulations reveal that the intermolecular interactions preferentially occur between specific cations and phosphate groups (P1, P4, and P5) of the inositol headgroup with better-matched kosmotropic/chaotropic characters consistent with the law of matching water affinities (LMWA). Ca is strongly attracted to P4/P5, while K preferentially binds to P1; Na interacts with both P4/P5 and P1. These specific interactions lead to the characteristic clustering patterns. Specificially, the size distributions and structures of PIP clusters generated by kosmotropic cations Ca and Na are bimodal, with a combination of small and large clusters, while there is little clustering in the presence of only chaotropic K; the largest clusters are obtained in systems with all three cations. The small-world network (a model with both local and long-range connections) best characterizes the clusters, followed by the random and the scale-free networks. More generally, the present results interpreted within the LMWA are consistent with the relative eukaryotic intracellular concentrations Ca ≪ Na < Mg < K; that is, concentrations of Ca and Na must be low to prevent damaging aggregation of lipids, DNA, RNA and phosphate-containing proteins.
由磷脂酰肌醇（4,5）-二磷酸（PI(4,5)P₂；PIP₂）介导的众多细胞功能涉及脂质的聚集以及与其他脂质的共定位。尽管阳离子介导的静电相互作用被视为主要的聚集机制，但分子间网络形成的离子特异性性质使得表征这些聚集体具有挑战性。在此，我们使用PIP₂单层的全原子分子动力学（MD）模拟和图论分析来深入了解这一现象。MD模拟表明，分子间相互作用优先发生在特定阳离子与肌醇头部基团的特定磷酸基团（P₁、P₄和P₅）之间，其具有与匹配水亲和力定律（LMWA）一致的更好匹配的促晶/促溶特性。Ca强烈吸引到P₄/P₅，而K优先结合到P₁；Na与P₄/P₅和P₁都相互作用。这些特定相互作用导致了特征性的聚集模式。具体而言，由促晶阳离子Ca和Na产生的PIP₂聚集体的尺寸分布和结构是双峰的，有小聚集体和大聚集体的组合，而仅存在促溶K时几乎没有聚集；在含有所有三种阳离子的系统中获得最大的聚集体。小世界网络（一种具有局部和远程连接的模型）最能表征这些聚集体，其次是随机网络和无标度网络。更一般地说，在LMWA范围内解释的当前结果与真核细胞内相对浓度Ca≪Na＜Mg＜K一致；也就是说，Ca和Na的浓度必须低以防止脂质、DNA、RNA和含磷酸盐蛋白质的有害聚集。
