Understanding the free-energy landscape of phase separation in lipid bilayers using molecular dynamics.
Understanding the free-energy landscape of phase separation in lipid bilayers using molecular dynamics.
复制标题
使用分子动力学了解脂质双层中相分离的自由能景观。
DOI：
10.1016/j.bpj.2023.09.012
复制
发表时间：
2023
影响因子：
3.4
通讯作者：
Grossfield,Alan
中科院分区：
文献类型：
--
作者：
Poruthoor,AshlinJ;Sharma,Akshara;Grossfield,Alan
细胞内的液-液相分离经常导致生物冷凝物，其可严重影响细胞内稳态。这种相分离事件发生在细胞的多个部分，包括细胞膜，其中“脂筏”假说假定形成漂浮在无序脂质海洋中的有序结构域。所产生的脂质结构域通常具有功能性作用。然而，脂质相分离的热力学及其对细胞功能和功能障碍的机械影响知之甚少。了解细胞膜中的这种复杂现象及其多种脂质组成是非常困难的。由于这些原因，可以概括类似行为的简单模型系统被广泛用于研究这一现象。尽管有这些简化，域形成的时间尺度和长度尺度对分子动力学（MD）模拟提出了挑战。因此，大多数MD研究集中在自发的脂质相分离-基本上测量分离时自由能变化的符号（但不是幅度）-而不是直接询问热力学。在这里，我们提出了一个概念验证的管道，可以直接测量这种自由能相结合的粗粒度MD与增强的采样协议，使用一种新的集体变量。这种方法将是一个有用的工具，以帮助连接相分离的热力学与机械的见解已经从MD模拟。
Liquid-liquid phase separation inside the cell often results in biological condensates that can critically affect cell homeostasis. Such phase separation events occur in multiple parts of cells, including the cell membranes, where the "lipid raft" hypothesis posits the formation of ordered domains floating in a sea of disordered lipids. The resulting lipid domains often have functional roles. However, the thermodynamics of lipid phase separation and their resulting mechanistic effects on cell function and dysfunction are poorly understood. Understanding such complex phenomena in cell membranes, with their diverse lipid compositions, is exceptionally difficult. For these reasons, simple model systems that can recapitulate similar behavior are widely used to study this phenomenon. Despite these simplifications, the timescale and length scales of domain formation pose a challenge for molecular dynamics (MD) simulations. Thus, most MD studies focus on spontaneous lipid phase separation—essentially measuring the sign (but not the amplitude) of the free-energy change upon separation—rather than directly interrogating the thermodynamics. Here, we propose a proof-of-concept pipeline that can directly measure this free energy by combining coarse-grained MD with enhanced sampling protocols using a novel collective variable. This approach will be a useful tool to help connect the thermodynamics of phase separation with the mechanistic insights already available from MD simulations.