Probing the rules governing domain formation and protein partitioning in membrane

波士顿大学的John E.Straub教授获得了化学部化学理论、模型和计算方法(CTMC)项目的支持，负责对脂膜结构的预测进行理论和计算研究。脂膜在细胞的组织和功能中起着关键作用。对脂膜的系统研究对于我们理解细胞功能的基本方面是必不可少的，包括细胞运输和信号传递。目前，最先进的计算模型无法捕捉膜结构和功能的关键方面。Straub小组正在开发膜和膜蛋白的新理论模型，希望在细胞计算建模方面达到一个新的现实水平。因此，这些方法的成功开发及其应用可能会对该领域产生变革。该项目包括对本科生和研究生的培训和指导，以及模拟方法、代码和数据集的开发。一本完整的《化学工作者的数学方法》教材正在编写中，将向教师和学生免费提供。分析具有非均相膜表面结构的类脂结构域的多组分蛋白质混合物的程序极具挑战性。为了与实验直接比较，有必要进行全原子模拟，因此自由能计算采用伞采样和能量表示法来提高速度和精度，并在二面体空间和自由体积空间进行模拟回火来增强构象采样。多组分混合物是复杂的，包含胆固醇、鞘脂、糖脂和其他在确定脂相结构域中重要的试剂。这项研究的目标是使用原子模型首次从头研究膜结构域的形成和膜蛋白的分配。这些模型通过对膜混合物中纳米膜结构和脂域之间蛋白质分配的平均实验测量进行了验证。这一奖项反映了NSF的法定使命，并通过使用基金会的智力优势和更广泛的影响审查标准进行评估，被认为值得支持。

Professor John E. Straub at Boston University is supported by an award from the Chemical Theory, Models and Computational Methods (CTMC) Program in the Chemistry Division to perform theoretical and computational research on predictions of the structure of the lipid membrane. The lipid membrane plays a key role in the organization and function of the cell. The systematic investigation of lipid membranes is essential to our understanding of fundamental aspects of cellular function, including cellular transport and signaling. At the present time, state-of-the-art computational models fail to capture key aspects of membrane structure and function. The Straub group is developing novel theoretical models of membrane and membrane proteins that aspire to a new level of realism in the computational modeling of the cell. As such, the successful development of the methods and their applications may be transformative to the field. This project includes the training and mentoring of undergraduate and graduate research students as well as the development of simulation methods, codes, and datasets. A complete textbook on the topic "Mathematical Methods for Chemists" is being developed that will be made freely available to instructors and students.The program of analyzing multi-component protein mixtures partitioning with lipid domains in heterogeneous membrane surface structure is extremely challenging. For direct comparison with experiment, it is necessary to perform all-atom simulations, so the free energy calculations use Umbrella Sampling and Energy Representation methods for speed and accuracy and Simulated Tempering in dihedral space and free volume space for enhanced conformational sampling. The multi-component mixtures are complex, containing cholesterol, sphingolipids, glycolipids and other agents important in determining lipid phase domains. The goal of this research is to enable the first de novo studies of membrane domain formation and membrane protein partitioning using atomistic models. The models are validated against average experimental measurements of nanoscopic membrane structures in membrane mixtures and protein partitioning between lipid domains.This award reflects NSF's statutory mission and has been deemed worthy of support through evaluation using the Foundation's intellectual merit and broader impacts review criteria.