Driving Force of Lipid Raft Formation: A Monte Carlo Simulation of Raft Mixture Phase Diagrams

脂筏结构域被认为参与重要的细胞功能。有人认为，它的形成纯粹是由于脂质-脂质相互作用，这是支持最近的实验证据表明，液体有序结构域可以复制合成脂质体含有不饱和磷脂酰胆碱（PC），鞘磷脂（SM），和胆固醇。 一个关键的问题是什么是脂筏形成的驱动力？ 目前的假说包括胆固醇和鞘磷脂的长饱和酰基链之间的强货车范德华吸引力、胆固醇和鞘脂之间的氢键以及烃链的熵效应。 在本项目中，将使用Monte Carlo模拟来再现DOPC/SM/胆固醇混合物的实验相图，通过该相图来检验假设并识别关键的分子相互作用。 具体而言，PI将使用成对和多体相互作用为每个假设建立明确的分子相互作用模型，并通过模拟PC/SM/胆固醇混合物中的脂筏相来定量检验这些假设。实验值的组成和数量的共存相和相互作用的大小将被用来判断的假设。PC/SM/胆固醇系统的整个相图将通过自由能模拟来构建，以使用不同脂质混合物系统的实验相图来定量识别头基和酰基链的贡献。 我们的目标是寻找一个清晰的物理模型和一组相互作用参数，可以密切再现实验相图。 脂筏是细胞膜结构域，含有膜蛋白、磷脂酰胆碱、鞘磷脂和胆固醇。 这些结构域被认为对细胞功能非常重要。 这项研究是第一次大规模的理论建模努力，以了解其形成机制。 该项目的成功将是对生物膜和脂质生物物理学领域的重大贡献，并将激发更多的实验和分子动力学模拟研究。 参与该项目的学生将接受脂质生物物理学，计算机模拟和使用Beowulf集群并行计算的讲座和实践培训。 这个建模项目与正在进行的实验研究计划相结合，将吸引更多的学生到德克萨斯理工大学，该大学拥有大量的少数民族学生人口，在地理上代表性不足。

Lipid raft domains are thought to be involved in important cell functions. It has been suggested that its formation is purely due to lipid-lipid interaction, which is supported by recent experimental evidence that the liquid-ordered domains can be reproduced on synthetic liposomes containing unsaturated phosphatidylcholine (PC), sphingomyelin (SM), and cholesterol. A crucial question is what is the driving force for lipid raft formation? Current hypotheses include a strong van der Waals attraction between cholesterol and the long saturated acyl chain of sphingomyelin, hydrogen bonding between cholesterol and sphingolipids and an entropy effect of hydrocarbon chains. In this project, Monte Carlo simulations will be used to reproduce the experimental phase diagram of DOPC/SM/cholesterol mixtures, through which the hypotheses will be tested and the key molecular interactions will be identified. Specifically, the PI will use both pairwise and multibody interactions to build explicit molecular interaction model for each hypothesis and quantitatively test these hypotheses by simulating lipid raft phase in PC/SM/cholesterol mixtures. Experimental values on composition and amount of coexisting phases and the magnitude of interaction will be used to judge the hypotheses. Entire phase diagrams of the PC/SM/cholesterol system will be constructed by free energy simulations to quantitatively identify the headgroup and acyl chain contributions using experimental phase diagrams of different lipid mixture systems. The goal is to search for a clear physical model and a set of interaction parameters that can closely reproduce the experimental phase diagram. Lipid rafts are cell membrane domains containing membrane proteins, phosphatidylcholine, sphingomyelin, and cholesterol. These domains are thought to be very important to cell functions. This research is the first large-scale theoretical modeling effort to understand the mechanism of its formation. The success of the project would be a significant contribution to the fields of biomembrane and lipid biophysics, and would stimulate more experimental and molecular dynamics simulation studies. Students involved in the project will receive lecture and hands-on training in lipid biophysics, computer simulation, and parallel computing using Beowulf cluster. This modeling project combining with the ongoing experimental research program would attract more students to Texas Tech University, which has a large minority student population and is geographically underrepresented.